ClinVar Genomic variation as it relates to human health
NM_207361.6(FREM2):c.8902G>A (p.Val2968Ile)
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_207361.6(FREM2):c.8902G>A (p.Val2968Ile)
Variation ID: 195789 Accession: VCV000195789.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.3 13: 39453010 (GRCh37) [ NCBI UCSC ] 13: 38878873 (GRCh38) [ 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 Jun 28, 2015 Apr 15, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_207361.6:c.8902G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_997244.4:p.Val2968Ile missense NC_000013.11:g.38878873G>A NC_000013.10:g.39453010G>A NG_008125.2:g.196838G>A - Protein change
- V2968I
- Other names
- -
- Canonical SPDI
- NC_000013.11:38878872:G:A
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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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0.00100 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00100
1000 Genomes Project 30x 0.00125
The Genome Aggregation Database (gnomAD) 0.00379
Exome Aggregation Consortium (ExAC) 0.00400
Trans-Omics for Precision Medicine (TOPMed) 0.00375
The Genome Aggregation Database (gnomAD), exomes 0.00406
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00477
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
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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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FREM2 | - | - |
GRCh38 GRCh37 |
1847 | 1907 |
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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Jun 3, 2022 | RCV000176440.5 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000224494.16 | |
Benign (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000989101.1 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001110834.4 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 8, 2022 | RCV002500488.1 | |
Likely benign (1) |
criteria provided, single submitter
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May 6, 2019 | RCV003917638.1 |
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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Likely Benign
(Sep 29, 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: SCV000281126.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Comment:
Converted during submission to Likely benign.
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Benign
(Dec 01, 2014)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000228096.5
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 1
Sex: mixed
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Benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Fraser syndrome 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139298.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Fraser syndrome 2
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001268316.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Sep 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001782781.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26275891) (less)
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Benign
(Jun 03, 2022)
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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: SCV002555646.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Variant summary: FREM2 c.8902G>A (p.Val2968Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: FREM2 c.8902G>A (p.Val2968Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 282828 control chromosomes in the gnomAD database, with 6 homozygotes. The variant occurs predominantly at a frequency of 0.0063 within the Non-Finnish European subpopulation in the gnomAD database, with 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in FREM2 causing Cryptophthalmos Syndrome phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Five ClinVar submitters have assessed the variant since 2014: three classified the variant as likely benign and two as benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Apr 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Isolated cryptophthalmia
Fraser syndrome 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002812629.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Benign
(Jan 31, 2024)
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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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Invitae
Accession: SCV001012437.5
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
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Likely benign
(May 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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FREM2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004729282.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004133069.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
FREM2: BP4, BS2
Number of individuals with the variant: 4
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001548862.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The FREM2 p.Val2968Ile variant was not identified in Cosmic but was identified in dbSNP (ID: rs116099212), ClinVar (classified as benign by EGL Genetic Diagnostics and … (more)
The FREM2 p.Val2968Ile variant was not identified in Cosmic but was identified in dbSNP (ID: rs116099212), ClinVar (classified as benign by EGL Genetic Diagnostics and likely benign by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 1149 of 282828 chromosomes (6 homozygous) at a frequency of 0.004063 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 811 of 129136 chromosomes (freq: 0.00628), South Asian in 154 of 30616 chromosomes (freq: 0.00503), Other in 28 of 7226 chromosomes (freq: 0.003875), European (Finnish) in 67 of 25122 chromosomes (freq: 0.002667), Latino in 61 of 35438 chromosomes (freq: 0.001721), African in 24 of 24974 chromosomes (freq: 0.000961), Ashkenazi Jewish in 3 of 10364 chromosomes (freq: 0.00029), and East Asian in 1 of 19952 chromosomes (freq: 0.00005). This variant was identified in the heterozygous state in one case with a prenatal diagnosis of laryngeal atresia/stenosis although the clinical significance of this variant is not known (Drury_2015_PMID:26275891). The p.Val2968 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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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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Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities. | Drury S | Prenatal diagnosis | 2015 | PMID: 26275891 |
http://exac.broadinstitute.org/variant/13-39453010-G-A | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FREM2 | - | - | - | - |
Text-mined citations for rs116099212 ...
HelpRecord last updated Apr 15, 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.