18-31071692-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_024422.6(DSC2):c.2038C>A(p.Arg680Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R680H) has been classified as Uncertain significance.
Frequency
Consequence
NM_024422.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.2038C>A | p.Arg680Ser | missense_variant | 13/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.2038C>A | p.Arg680Ser | missense_variant | 13/17 | ||
DSC2 | NM_001406506.1 | c.1609C>A | p.Arg537Ser | missense_variant | 13/16 | ||
DSC2 | NM_001406507.1 | c.1609C>A | p.Arg537Ser | missense_variant | 13/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.2038C>A | p.Arg680Ser | missense_variant | 13/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.2038C>A | p.Arg680Ser | missense_variant | 13/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.1609C>A | p.Arg537Ser | missense_variant | 14/17 | ||||
DSC2 | ENST00000682357.1 | c.1609C>A | p.Arg537Ser | missense_variant | 13/16 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250910Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135598
GnomAD4 exome AF: 0.0000280 AC: 41AN: 1461796Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 727190
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74328
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 20, 2022 | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 680 of the DSC2 protein (p.Arg680Ser). This variant is present in population databases (rs757253682, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 418603). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 06, 2023 | This missense variant replaces arginine with serine at codon 680 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSC2-related disorders in the literature. This variant has been identified in 2/250910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 06, 2019 | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 418603; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 17, 2023 | The p.R680S variant (also known as c.2038C>A), located in coding exon 13 of the DSC2 gene, results from a C to A substitution at nucleotide position 2038. The arginine at codon 680 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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 | Aug 14, 2023 | This missense variant replaces arginine with serine at codon 680 of the DSC2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/250910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at