rs1555639134
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_024422.6(DSC2):c.996T>G(p.Tyr332*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
DSC2
NM_024422.6 stop_gained
NM_024422.6 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 0.290
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 Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 18-31083007-A-C is Pathogenic according to our data. Variant chr18-31083007-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 468388.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSC2 | NM_024422.6 | c.996T>G | p.Tyr332* | stop_gained | 8/16 | ENST00000280904.11 | NP_077740.1 | |
DSC2 | NM_004949.5 | c.996T>G | p.Tyr332* | stop_gained | 8/17 | NP_004940.1 | ||
DSC2 | NM_001406506.1 | c.567T>G | p.Tyr189* | stop_gained | 8/16 | NP_001393435.1 | ||
DSC2 | NM_001406507.1 | c.567T>G | p.Tyr189* | stop_gained | 8/17 | NP_001393436.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSC2 | ENST00000280904.11 | c.996T>G | p.Tyr332* | stop_gained | 8/16 | 1 | NM_024422.6 | ENSP00000280904.6 | ||
DSC2 | ENST00000251081.8 | c.996T>G | p.Tyr332* | stop_gained | 8/17 | 1 | ENSP00000251081.6 | |||
DSC2 | ENST00000648081.1 | c.567T>G | p.Tyr189* | stop_gained | 9/17 | ENSP00000497441.1 | ||||
DSC2 | ENST00000682357.1 | c.567T>G | p.Tyr189* | stop_gained | 8/16 | ENSP00000507826.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 11 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 07, 2017 | While this particular variant has not been reported in the literature, loss-of-function variants in DSC2 are known to be pathogenic (PMID: 23911551). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal at codon 332 (p.Tyr332*) of the DSC2 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at