rs121913007
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001943.5(DSG2):c.918G>A(p.Trp306Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,838 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). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001943.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.918G>A | p.Trp306Ter | stop_gained | 8/15 | ENST00000261590.13 | |
DSG2 | XM_047437315.1 | c.384G>A | p.Trp128Ter | stop_gained | 9/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.918G>A | p.Trp306Ter | stop_gained | 8/15 | 1 | NM_001943.5 | P1 | |
DSG2 | ENST00000682087.2 | n.749G>A | non_coding_transcript_exon_variant | 6/6 | |||||
DSG2 | ENST00000683614.2 | n.749G>A | non_coding_transcript_exon_variant | 6/7 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461838Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727222
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 10 Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2006 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | KardioGenetik, Herz- und Diabeteszentrum NRW | Mar 14, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 31, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 16811). This variant is also known as W305X. This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 16773573). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp306*) in the DSG2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 17105751, 31386562). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Dec 28, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2023 | Variant, reported as c.915G>A (W305X) using alternate nomenclature, was observed in the compound heterozygous state with DSG2 R48H in an individual with ARVC, as well as in the heterozygous state in two unaffected relatives (PMID: 16773573); Observed in an individual with ARVC (PMID: 31386562); Not observed at a significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20857253, 25525159, 20031617, 31402444, 31386562, 16773573) - |
Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 25, 2021 | - - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This variant changes 1 nucleotide in exon 8 of the DSG2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant (referred to as c.915G>A, W305X) has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy, who also carried another pathogenic variant in the DSG2 gene that could explain the observed phenotype (PMID: 16773573). This variant has been observed in the proband's unaffected mother and sister as well. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical relevance of loss-of-function DSC2 truncation and splice variants in autosomal dominant arrhythmogenic cardiomyopathy is not yet clearly established. 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