rs377700521
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_024422.6(DSC2):c.2446G>A(p.Val816Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_024422.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.2446G>A | p.Val816Met | missense_variant | 15/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.2446G>A | p.Val816Met | missense_variant | 15/17 | ||
DSC2 | NM_001406506.1 | c.2017G>A | p.Val673Met | missense_variant | 15/16 | ||
DSC2 | NM_001406507.1 | c.2017G>A | p.Val673Met | missense_variant | 15/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.2446G>A | p.Val816Met | missense_variant | 15/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.2446G>A | p.Val816Met | missense_variant | 15/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.2017G>A | p.Val673Met | missense_variant | 16/17 | ||||
DSC2 | ENST00000682357.1 | c.2017G>A | p.Val673Met | missense_variant | 15/16 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251206Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135774
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461856Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727224
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74410
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 816 of the DSC2 protein (p.Val816Met). This variant is present in population databases (rs377700521, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy or arrhythmia (PMID: 27532257, 31484862). ClinVar contains an entry for this variant (Variation ID: 46181). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSC2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 11, 2012 | Variant classified as Uncertain Significance - Favor Benign. The Val816Met varia nt (DSC2) has not been reported in the literature nor previously identified by o ur laboratory. Computational analyses (biochemical amino acid properties, conser vation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Val816Met variant may n ot impact the protein, though this information is not predictive enough to rule out pathogenicity. Additional studies are needed to fully assess its clinical si gnificance. - |
DSC2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 11, 2023 | The DSC2 c.2446G>A variant is predicted to result in the amino acid substitution p.Val816Met. This variant was reported in individuals with dilated cardiomyopathy (Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221). This variant has also been reported in a patient with arrhythmia and in his unaffected father (Chen et al. 2019. PubMed ID: 31484862). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-28648922-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 28, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at