rs397517391
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_024422.6(DSC2):c.149G>A(p.Gly50Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000673 in 1,605,196 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).
Frequency
Consequence
NM_024422.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.149G>A | p.Gly50Asp | missense_variant | Exon 2 of 16 | ENST00000280904.11 | NP_077740.1 | |
DSC2 | NM_004949.5 | c.149G>A | p.Gly50Asp | missense_variant | Exon 2 of 17 | NP_004940.1 | ||
DSC2 | NM_001406506.1 | c.-281G>A | 5_prime_UTR_variant | Exon 2 of 16 | NP_001393435.1 | |||
DSC2 | NM_001406507.1 | c.-281G>A | 5_prime_UTR_variant | Exon 2 of 17 | NP_001393436.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.149G>A | p.Gly50Asp | missense_variant | Exon 2 of 16 | 1 | NM_024422.6 | ENSP00000280904.6 | ||
DSC2 | ENST00000251081.8 | c.149G>A | p.Gly50Asp | missense_variant | Exon 2 of 17 | 1 | ENSP00000251081.6 | |||
DSC2 | ENST00000648081.1 | c.-318G>A | 5_prime_UTR_variant | Exon 2 of 17 | ENSP00000497441.1 | |||||
DSC2 | ENST00000682357.1 | c.-281G>A | 5_prime_UTR_variant | Exon 2 of 16 | ENSP00000507826.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151982Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251338Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135840
GnomAD4 exome AF: 0.0000729 AC: 106AN: 1453214Hom.: 0 Cov.: 29 AF XY: 0.0000678 AC XY: 49AN XY: 723184
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151982Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74226
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
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This missense variant replaces glycine with aspartic acid at codon 50 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 9/282702 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 specified Uncertain:1
The Gly50Asp variant in DSC2 has not been reported in the literature nor previou sly identified by our laboratory. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is need ed to fully assess the clinical significance of this variant. -
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 50 of the DSC2 protein (p.Gly50Asp). This variant is present in population databases (rs397517391, gnomAD 0.008%). 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: 46166). 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 expected to disrupt DSC2 protein function with a positive 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. -
not provided Uncertain:1
Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1
This missense variant replaces glycine with aspartic acid at codon 50 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 cardiovascular disorders in the literature. This variant has been identified in 9/282702 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
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