rs121913012
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_001943.5(DSG2):c.991G>A(p.Glu331Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,044 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: 0.000012 ( 0 hom. )
Consequence
DSG2
NM_001943.5 missense
NM_001943.5 missense
Scores
8
5
6
Clinical Significance
Conservation
PhyloP100: 9.02
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 Uncertain_significance. Variant got 4 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.971
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.991G>A | p.Glu331Lys | missense_variant | 8/15 | ENST00000261590.13 | |
DSG2 | XM_047437315.1 | c.457G>A | p.Glu153Lys | missense_variant | 9/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.991G>A | p.Glu331Lys | missense_variant | 8/15 | 1 | NM_001943.5 | P1 | |
DSG2 | ENST00000682087.2 | n.822G>A | non_coding_transcript_exon_variant | 6/6 | |||||
DSG2 | ENST00000683614.2 | n.822G>A | non_coding_transcript_exon_variant | 6/7 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249402Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135310
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461842Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9AN XY: 727222
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 10 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 07, 2006 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 331 of the DSG2 protein (p.Glu331Lys). This variant is present in population databases (rs121913012, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 24070718, 28471438, 30830208). ClinVar contains an entry for this variant (Variation ID: 16816). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Arrhythmogenic right ventricular cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces glutamic acid with lysine at codon 331 of the DSG2 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 three unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 16505173, 21606390, 29750433) and in three unaffected relatives from one of the families (PMID: 16505173, 24070718, 26138720). One of the probands was compound heterozygous with a splice variant (PMID 26138720). This variant has been identified in 4/249402 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2015 | The c.991G>A (p.Glu331Lys) missense variant changes evolutionary conserved Glu to Lys, which changes the charge from negative to positive. 3/4 in silico tools predict this variant to be damaging. This variant lies in cadherin 3 domain (source ARVC db) and other missense changes have also been detected in and around this codon such as p.D326V, p.N330D, p.I333T and p.T335A (source: HGMD) in ARVC patients. This suggests that this variant may alter protein functionality. The variant is found in only 3 alleles across 120630 chromosomes in ExAC. Although the allele frequency in general population is lower than the maximal expected allele frequency based on the disease prevalence of ARVC, the possibility of this variant being a rare polymorphism cannot be ruled out. Two studies reported this variant in two ARVD families; however, segregation analysis in one family does not prove the variant as a high penetrance disease-causing variant. - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 06, 2022 | This missense variant replaces glutamic acid with lysine at codon 331 of the DSG2 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 three unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 16505173, 21606390, 29750433) and in three unaffected relatives from one of the families (PMID: 16505173, 24070718, 26138720). One of the probands was compound heterozygous with a splice variant (PMID 26138720). This variant has been identified in 4/249402 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Sep 08, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 14, 2021 | Identified in two siblings with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, both individuals also harbor a splice site variant in the DSG2 gene (Pilichou et al., 2006); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 16816; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31402444, 16505173) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Gain of methylation at E331 (P = 0.0135);
MVP
MPC
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