rs397517405
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_024422.6(DSC2):āc.844T>Cā(p.Tyr282His) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,848 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 Uncertain significance (ā ā ).
Frequency
Consequence
NM_024422.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.844T>C | p.Tyr282His | missense_variant | Exon 7 of 16 | ENST00000280904.11 | NP_077740.1 | |
DSC2 | NM_004949.5 | c.844T>C | p.Tyr282His | missense_variant | Exon 7 of 17 | NP_004940.1 | ||
DSC2 | NM_001406506.1 | c.415T>C | p.Tyr139His | missense_variant | Exon 7 of 16 | NP_001393435.1 | ||
DSC2 | NM_001406507.1 | c.415T>C | p.Tyr139His | missense_variant | Exon 7 of 17 | NP_001393436.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.844T>C | p.Tyr282His | missense_variant | Exon 7 of 16 | 1 | NM_024422.6 | ENSP00000280904.6 | ||
DSC2 | ENST00000251081.8 | c.844T>C | p.Tyr282His | missense_variant | Exon 7 of 17 | 1 | ENSP00000251081.6 | |||
DSC2 | ENST00000648081.1 | c.415T>C | p.Tyr139His | missense_variant | Exon 8 of 17 | ENSP00000497441.1 | ||||
DSC2 | ENST00000682357.1 | c.415T>C | p.Tyr139His | missense_variant | Exon 7 of 16 | ENSP00000507826.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251378Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135858
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461848Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727226
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
The Tyr282His variant in DSC2 has not been reported in the literature nor previo usly identified in large and broad European American and African American popula tions by NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). This low frequency is consistent with a disease causing role but insufficient to est ablish this with confidence. Computational analyses (biochemical amino acid prop erties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to dete rmine pathogenicity. However, this variant is present in 2 reportedly unaffecte d relatives and has not been observed in isolation in an affected individual, ra ising the possibility that only modifies disease or may not be disease causing. Additional information is needed to fully assess the clinical significance of th e Tyr282His variant. -
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 282 of the DSC2 protein (p.Tyr282His). This variant is present in population databases (rs397517405, gnomAD 0.003%). 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: 46198). 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. -
Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1
This missense variant replaces tyrosine with histidine at codon 282 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 not been reported in individuals affected with DSC2-related disorders in the literature. This variant has been identified in 1/251378 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at