ClinVar Genomic variation as it relates to human health
NM_005188.4(CBL):c.869+4A>G
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005188.4(CBL):c.869+4A>G
Variation ID: 45211 Accession: VCV000045211.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.3 11: 119274957 (GRCh38) [ NCBI UCSC ] 11: 119145667 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 27, 2015 May 1, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005188.4:c.869+4A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000011.10:g.119274957A>G NC_000011.9:g.119145667A>G NG_016808.1:g.73678A>G LRG_608:g.73678A>G LRG_608t1:c.869+4A>G - Protein change
- Other names
- -
- Canonical SPDI
- NC_000011.10:119274956:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.02416 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00503
Exome Aggregation Consortium (ExAC) 0.00624
The Genome Aggregation Database (gnomAD) 0.02038
Trans-Omics for Precision Medicine (TOPMed) 0.02170
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.02364
1000 Genomes Project 0.02416
1000 Genomes Project 30x 0.02498
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CBL | No evidence available | No evidence available |
GRCh38 GRCh37 |
1424 | 1573 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign (2) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000049224.13 | |
Benign (5) |
criteria provided, multiple submitters, no conflicts
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Sep 9, 2019 | RCV000038366.14 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Nov 20, 2023 | RCV000224916.8 | |
Benign (1) |
criteria provided, single submitter
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Jan 13, 2018 | RCV000339761.5 | |
Benign (1) |
criteria provided, single submitter
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Jun 21, 2021 | RCV001813350.3 | |
Benign (1) |
criteria provided, single submitter
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Aug 22, 2019 | RCV002371836.2 | |
Benign (1) |
criteria provided, single submitter
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Jul 7, 2023 | RCV003315565.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000310880.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Benign
(Mar 19, 2012)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000062038.5
First in ClinVar: May 03, 2013 Last updated: Oct 02, 2016 |
Comment:
c.869+4A>G in Intron 05 of CBL: This variant is not expected to have clinical si gnificance because it has been identified in 6.8% (255/3736) of … (more)
c.869+4A>G in Intron 05 of CBL: This variant is not expected to have clinical si gnificance because it has been identified in 6.8% (255/3736) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs77284821). (less)
Number of individuals with the variant: 19
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Benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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CBL-related disorder
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000367755.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Benign
(Sep 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362304.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: CBL c.869+4A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: CBL c.869+4A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.005 in 251474 control chromosomes, predominantly at a frequency of 0.07 within the African or African-American subpopulation in the gnomAD database, including 40 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 28000 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBL causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.869+4A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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Benign
(Aug 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002684122.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Benign
(May 14, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280906.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
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Benign
(May 04, 2012)
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criteria provided, single submitter
Method: clinical testing
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Rasopathy
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000077238.3
First in ClinVar: Jul 03, 2013 Last updated: May 27, 2015 |
Comment:
The variant is found in NOONAN panel(s).
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Benign
(Jun 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome and Noonan-related syndrome
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002060505.1
First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022 |
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Benign
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Juvenile myelomonocytic leukemia
Affected status: yes
Allele origin:
germline
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004016974.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
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Benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000555937.9
First in ClinVar: May 27, 2015 Last updated: Feb 14, 2024 |
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Benign
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003799332.3
First in ClinVar: Feb 13, 2023 Last updated: Feb 20, 2024 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807751.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954365.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Impact of genomic alterations on outcomes in myelofibrosis patients undergoing JAK1/2 inhibitor therapy. | Spiegel JY | Blood advances | 2017 | PMID: 29296819 |
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. | Arber DA | Blood | 2016 | PMID: 27069254 |
Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling. | Rathinam C | Cancer cell | 2010 | PMID: 20951944 |
Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. | Sanada M | Nature | 2009 | PMID: 19620960 |
Text-mined citations for rs77284821 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.