18-31079973-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_024422.6(DSC2):c.1537G>T(p.Asp513Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,704 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D513G) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.1537G>T | p.Asp513Tyr | missense_variant | 11/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.1537G>T | p.Asp513Tyr | missense_variant | 11/17 | ||
DSC2 | NM_001406506.1 | c.1108G>T | p.Asp370Tyr | missense_variant | 11/16 | ||
DSC2 | NM_001406507.1 | c.1108G>T | p.Asp370Tyr | missense_variant | 11/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.1537G>T | p.Asp513Tyr | missense_variant | 11/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.1537G>T | p.Asp513Tyr | missense_variant | 11/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.1108G>T | p.Asp370Tyr | missense_variant | 12/17 | ||||
DSC2 | ENST00000682357.1 | c.1108G>T | p.Asp370Tyr | missense_variant | 11/16 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152138Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251034Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135696
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461566Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727078
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74310
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 03, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 12, 2019 | This missense variant replaces aspartic acid with tyrosine at codon 513 of the DSC2 protein. Computational prediction tool 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/282436 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
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 15, 2014 | The Asp513Tyr variant in DSC2 has not been previously reported in individuals wi th cardiomyopathy, but has been identified in 1/4406 of African American chromos omes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Computational prediction tools and conservation analysis don?t provide strong ev idence for or against an impact to the protein. In summary, the clinical signifi cance of the Asp513Tyr variant is uncertain. - |
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 04, 2023 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 163188). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is present in population databases (rs373324195, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 513 of the DSC2 protein (p.Asp513Tyr). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 04, 2021 | The p.D513Y variant (also known as c.1537G>T), located in coding exon 11 of the DSC2 gene, results from a G to T substitution at nucleotide position 1537. The aspartic acid at codon 513 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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 | Jun 28, 2023 | This missense variant replaces aspartic acid with tyrosine at codon 513 of the DSC2 protein. Computational prediction tool 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/282436 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