18-31068931-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_024422.6(DSC2):c.2471C>T(p.Ser824Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000508 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S824A) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.2471C>T | p.Ser824Leu | missense_variant | 15/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.2471C>T | p.Ser824Leu | missense_variant | 15/17 | ||
DSC2 | NM_001406506.1 | c.2042C>T | p.Ser681Leu | missense_variant | 15/16 | ||
DSC2 | NM_001406507.1 | c.2042C>T | p.Ser681Leu | missense_variant | 15/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.2471C>T | p.Ser824Leu | missense_variant | 15/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.2471C>T | p.Ser824Leu | missense_variant | 15/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.2042C>T | p.Ser681Leu | missense_variant | 16/17 | ||||
DSC2 | ENST00000682357.1 | c.2042C>T | p.Ser681Leu | missense_variant | 15/16 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000916 AC: 23AN: 251032Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135706
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461752Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 727172
GnomAD4 genome AF: 0.000164 AC: 25AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74410
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular cardiomyopathy Uncertain:2
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Nov 30, 2015 | - - |
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 01, 2023 | This missense variant replaces serine with leucine at codon 824 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 two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495, 24832006). This variant was also detected in a post-mortem heart tissue sample from an individual with clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (PMID: 24832006). This variant has also been identified in 29/282414 chromosomes (18/24954 African 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. - |
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 | Feb 05, 2024 | This missense variant replaces serine with leucine at codon 824 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 two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495, 24832006). This variant was also detected in a post-mortem heart tissue sample from an individual with clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (PMID: 24832006). This variant has also been identified in 29/282414 chromosomes (18/24954 African 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
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 18, 2023 | This alteration is classified as 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