chr18-31498252-A-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2
The NM_001943.5(DSG2):c.1A>T(p.Met1?) variant causes a start lost 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
DSG2
NM_001943.5 start_lost
NM_001943.5 start_lost
Scores
5
3
8
Clinical Significance
Conservation
PhyloP100: 1.20
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
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_001943.5 (DSG2) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 657863
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.1A>T | p.Met1? | start_lost | 1/15 | ENST00000261590.13 | |
DSG2 | XM_047437315.1 | c.-572A>T | 5_prime_UTR_variant | 1/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.1A>T | p.Met1? | start_lost | 1/15 | 1 | NM_001943.5 | P1 | |
DSG2 | ENST00000683654.1 | c.1A>T | p.Met1? | start_lost | 1/7 | ||||
DSG2 | ENST00000682241.2 | c.1A>T | p.Met1? | start_lost | 1/7 | ||||
DSG2 | ENST00000585206.1 | c.1A>T | p.Met1? | start_lost | 1/6 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1106802Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 526228
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1106802
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Cov.:
30
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0
AN XY:
526228
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 07, 2020 | This variant alters the translation initiation codon of the DSG2 mRNA. An alternate in-frame methionine downstream of the initiator methionine occurs at codon 179 in extracellular cadherin domain 2, after signal peptide and propeptide. This variant is expected to disrupt translation initiation and result in an absent or truncated protein product. To our knowledge, functional studies have not been reported for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different DNA changes (c.3G>A and c.3G>C) with the same protein consequence (p.Met1?) have been reported in a few individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 17105751, 20829228). Although there is a suspicion for a pathogenic role, clinical relevance of loss-of-function DSC2 truncation and splice variants in autosomal dominant arrhythmogenic right ventricular 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;D
Polyphen
P;.
Vest4
MutPred
Loss of catalytic residue at M1 (P = 0.0212);Loss of catalytic residue at M1 (P = 0.0212);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
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
Publications
No publications associated with this variant yet.