VCV000143932.5 - ClinVar

NM_001080449.3(DNA2):c.3114+6del

Germline

Classification

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.

(2)

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.

Pathogenic/Likely pathogenic

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001080449.3(DNA2):c.3114+6del

Variation ID: 143932 Accession: VCV000143932.5

Type and length

Deletion, 1 bp

Location

Cytogenetic: 10q21.3 10: 68416703 (GRCh38) [ NCBI UCSC ] 10: 70176460 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Mar 10, 2015	May 12, 2024	Feb 1, 2014

HGVS

Nucleotide	Protein	Molecular consequence
NM_001080449.3:c.3114+6del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001080449.2:c.3114+6delC
NC_000010.11:g.68416704del
NC_000010.10:g.70176461del
NG_034247.1:g.60271del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000010.11:68416702:GG:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA170539 OMIM: 601810.0004 dbSNP: rs587777614 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 24389050 to determine the location of this allele on the current reference sequence. In Table 1 this is called NM_001080449.2:c.3372+6delC; in Fig. 3 it is called NM_001080449.2:c.3114+6delC, which corresponds to the given DNA sequence chromatogram.

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
Gene	OMIM	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.
DNA2		-	-	GRCh38 GRCh37	773	804

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.
Seckel syndrome 8	Pathogenic (1)	no assertion criteria provided	Feb 1, 2014	RCV000133461.7
Ateleiotic dwarfism	Likely pathogenic (1)	no assertion criteria provided	-	RCV000162161.5

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.
Pathogenic (Feb 01, 2014)	no assertion criteria provided Method: literature only	SECKEL SYNDROME 8 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000188496.6 First in ClinVar: Aug 21, 2014 Last updated: May 12, 2024	Publications: PubMed (1) PubMed: 24389050 Comment on evidence: In an 18-year-old uncle and 9-year-old niece, both born of consanguineous marriages, with short stature and strikingly similar facial features consistent with Seckel syndrome (SCKL8; … (more) In an 18-year-old uncle and 9-year-old niece, both born of consanguineous marriages, with short stature and strikingly similar facial features consistent with Seckel syndrome (SCKL8; 615807), Shaheen et al. (2014) identified homozygosity for a 1-bp deletion (c.3372+6delC) in intron 20 of the DNA2 gene, predicted to cause truncation of 1 transcript and abnormal splicing of another 2 transcripts. The mutation segregated with disease in the family and was not found in 250 local Saudi exomes, 131 Saudi controls by direct sequencing (including 31 tribe-specific controls), or in the EVS database. RT-PCR confirmed the abnormal splicing, revealing 5 aberrant transcripts that all shared the same abnormal donor site but that each had a different acceptor site; all 5 predicted a frameshift and/or truncation. Western blot analysis showed an approximately 50% reduction in protein level compared to controls. Patient fibroblasts exhibited key features of senescence, being remarkably larger and flatter than control fibroblasts; senescence assay showed blue beta-galactosidase staining in addition to the characteristic 'fried egg' appearance. In addition, comet tails were significantly longer in patient cells than controls, suggestive of marked DNA damage sensitivity; the phenotype was rescued by exogenous expression of DNA2. Shaheen et al. (2014) noted that both parental pairs in the extended family had had numerous miscarriages, suggesting that severe reduction in DNA2 may be incompatible with life. (less)
Likely pathogenic (Dec 01, 2014)	no assertion criteria provided (research) Method: research	Primordial dwarfism Affected status: yes Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Study: Genomic Analysis of Primordial Dwarfism Reveals Novel Disease Genes Accession: SCV000196447.1 First in ClinVar: Mar 10, 2015 Last updated: Mar 10, 2015	Publications: PubMed (1) PubMed: 25558065

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

Title	Author	Journal	Year	Link
Genomic analysis of primordial dwarfism reveals novel disease genes.	Shaheen R	Genome research	2014	PMID: 24389050

Text-mined citations for rs587777614 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Aug 04, 2024

ClinVar Genomic variation as it relates to human health

NM_001080449.3(DNA2):c.3114+6del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587777614 ...