rs375410133
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3
The NM_024422.6(DSC2):c.395G>A(p.Arg132His) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132C) 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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.395G>A | p.Arg132His | missense_variant | 4/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.395G>A | p.Arg132His | missense_variant | 4/17 | ||
DSC2 | NM_001406506.1 | c.-35G>A | 5_prime_UTR_variant | 4/16 | |||
DSC2 | NM_001406507.1 | c.-35G>A | 5_prime_UTR_variant | 4/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.395G>A | p.Arg132His | missense_variant | 4/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.395G>A | p.Arg132His | missense_variant | 4/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.-35G>A | 5_prime_UTR_variant | 5/17 | |||||
DSC2 | ENST00000682357.1 | c.-35G>A | 5_prime_UTR_variant | 4/16 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152110Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251188Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135772
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461708Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727158
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74302
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 20, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 25, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 132 of the DSC2 protein (p.Arg132His). This variant is present in population databases (rs375410133, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy (PMID: 29750433). ClinVar contains an entry for this variant (Variation ID: 468383). 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: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C25"). 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 | Mar 22, 2023 | This missense variant replaces arginine with histidine at codon 132 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic cardiomyopathy (PMID: 29750433). This variant has been identified in 9/282578 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 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 04, 2019 | The DSC2 c.395G>A; p.Arg132His variant (rs375410133) is reported in the literature in an individual affected with arrhythmogenic cardiomyopathy that also carried a second missense variant in DSC2 (Chen 2018). The p.Arg132His variant is found on only nine chromosomes (9/282578 alleles) in the Genome Aggregation Database. The arginine at codon 132 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another amino acid substitution at this codon (p.Arg132Cys) has been reported in an individual with arrhythmogenic cardiomyopathy, although its clinical significance was not demonstrated (Fressart 2010). Given the lack of clinical and functional data, the significance of the p.Arg132His variant is uncertain at this time. References: Chen K et al. Absence of a primary role for TTN missense variants in arrhythmogenic cardiomyopathy: From a clinical and pathological perspective. Clin Cardiol. 2018 May;41(5):615-622. Fressart V et al. Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice. Europace. 2010 Jun;12(6):861-8. - |
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 26, 2023 | This missense variant replaces arginine with histidine at codon 132 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic cardiomyopathy (PMID: 29750433). This variant has been identified in 9/282578 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 23, 2024 | This alteration is classified as likely 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at