18-31082955-C-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_024422.6(DSC2):c.1048G>T(p.Asp350Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,396 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 (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
DSC2
NM_024422.6 missense
NM_024422.6 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 6.47
Genes affected
DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.1048G>T | p.Asp350Tyr | missense_variant | 8/16 | ENST00000280904.11 | |
DSC2 | NM_004949.5 | c.1048G>T | p.Asp350Tyr | missense_variant | 8/17 | ||
DSC2 | NM_001406506.1 | c.619G>T | p.Asp207Tyr | missense_variant | 8/16 | ||
DSC2 | NM_001406507.1 | c.619G>T | p.Asp207Tyr | missense_variant | 8/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.1048G>T | p.Asp350Tyr | missense_variant | 8/16 | 1 | NM_024422.6 | P1 | |
DSC2 | ENST00000251081.8 | c.1048G>T | p.Asp350Tyr | missense_variant | 8/17 | 1 | |||
DSC2 | ENST00000648081.1 | c.619G>T | p.Asp207Tyr | missense_variant | 9/17 | ||||
DSC2 | ENST00000682357.1 | c.619G>T | p.Asp207Tyr | missense_variant | 8/16 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251044Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135706
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461216Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726918
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74346
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 04, 2015 | The p.Asp350Tyr variant in DSC2 has been reported in 1 Caucasian adult with prob able ARVC (diagnosed upon myocardial biopsy) as well as two siblings with abnorm al ECGs (Bhuiyan 2009). This variant has also been identified in 1/10436 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org). Computational prediction tools and conservation analysis suggest that i t may impact the protein, though this information is not predictive enough to de termine pathogenicity. In summary, the clinical significance of the p.Asp350Tyr variant is uncertain. - |
Arrhythmogenic right ventricular dysplasia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 07, 2021 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 15, 2020 | This missense variant replaces aspartic acid with tyrosine at codon 350 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 probably arrhythmogenic right ventricular cardiomyopathy as well as two siblings with abnormal ECGs (PMID: 20031616). This variant has also been reported in an individual without a diagnosis of arrhythmogenic right ventricular cardiomyopathy (PMID: 28471438). This variant has been identified in 2/282446 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 | GeneDx | Aug 15, 2019 | Reported in one female with a probable diagnosis of ARVC per task force criteria in published literature (Bhuiyan et al., 2009); this variant was also found in her two siblings with positive findings on signal-averaged electrocardiogram; Also identified as an incidental finding in 1/30,716 individuals who underwent exome sequencing (Haggerty et al., 2017); although a follow-up cardiac evaluation was not reported; Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 228620; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20031616, 23071725, 28471438, 31402444) - |
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 | Dec 16, 2022 | This missense variant replaces aspartic acid with tyrosine at codon 350 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 probably arrhythmogenic right ventricular cardiomyopathy as well as two siblings with abnormal ECGs (PMID: 20031616). This variant has also been reported in an individual without a diagnosis of arrhythmogenic right ventricular cardiomyopathy (PMID: 28471438). This variant has been identified in 2/282446 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Uncertain
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;.
Polyphen
D;D;.
Vest4
MutPred
Loss of phosphorylation at T354 (P = 0.207);Loss of phosphorylation at T354 (P = 0.207);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at