18-31524815-C-A
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001943.5(DSG2):c.941C>A(p.Ser314*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,828 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 Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
DSG2
NM_001943.5 stop_gained
NM_001943.5 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 4.19
Genes affected
DSG2 (HGNC:3049): (desmoglein 2) This gene encodes a member of the desmoglein family and cadherin cell adhesion molecule superfamily of proteins. Desmogleins are calcium-binding transmembrane glycoprotein components of desmosomes, cell-cell junctions between epithelial, myocardial, and other cell types. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This gene is present in a gene cluster with other desmoglein gene family members on chromosome 18. Mutations in this gene have been associated with arrhythmogenic right ventricular dysplasia, familial, 10. [provided by RefSeq, Jan 2016]
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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 18-31524815-C-A is Pathogenic according to our data. Variant chr18-31524815-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44332.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.941C>A | p.Ser314* | stop_gained | 8/15 | ENST00000261590.13 | NP_001934.2 | |
DSG2 | XM_047437315.1 | c.407C>A | p.Ser136* | stop_gained | 9/16 | XP_047293271.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.941C>A | p.Ser314* | stop_gained | 8/15 | 1 | NM_001943.5 | ENSP00000261590.8 | ||
DSG2 | ENST00000682087.2 | n.772C>A | non_coding_transcript_exon_variant | 6/6 | ||||||
DSG2 | ENST00000683614.2 | n.772C>A | non_coding_transcript_exon_variant | 6/7 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461828Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 727210
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 20, 2012 | The Ser314X variant has not been reported in the literature but has been previou sly identified in one individual with ARVC by our laboratory. This nonsense vari ant leads to a premature termination codon at position 324, which is predicted t o lead to a truncated or absent protein. In summary, this variant is likely to b e pathogenic, though segregation studies and functional analyses are required to fully establish the pathogenicity of this variant. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
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