18-31524754-A-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBS1_SupportingBS2

The NM_001943.5(DSG2):c.880A>G(p.Lys294Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,614,090 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 2 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:11

Conservation

PhyloP100: 4.20

Variant links:

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]

DSG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000363 (53/1461868) while in subpopulation MID AF= 0.00104 (6/5768). AF 95% confidence interval is 0.000453. There are 2 homozygotes in gnomad4_exome. There are 33 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5 link	c.880A>G	p.Lys294Glu	missense_variant	Exon 8 of 15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 link	c.346A>G	p.Lys116Glu	missense_variant	Exon 9 of 16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSG2	ENST00000261590.13 link	c.880A>G	p.Lys294Glu	missense_variant	Exon 8 of 15	1	NM_001943.5	ENSP00000261590.8	Q14126
DSG2	ENST00000682087.2 link	n.711A>G		non_coding_transcript_exon_variant	Exon 6 of 6				A0A804HLK9
DSG2	ENST00000683614.2 link	n.711A>G		non_coding_transcript_exon_variant	Exon 6 of 7				A0A804HJ09

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

249384

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000248

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Jan 10, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DSG2 c.880A>G; p.Lys294Glu variant (rs752432726; ClinVar ID 199803) has been reported in a single individual with arrhythmogenic right ventricular cardiomyopathy (Pilichou 2006); however, functional studies of this variant found no defects in prodomain cleavage, adhesion properties, or cellular localization compared to the wild-type protein (Gaertner 2012). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.002% (identified on 6 out of 277,042 chromosomes). The lysine at position 294 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Lys294Glu variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Lys294Glu variant cannot be determined with certainty. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1Uncertain:1

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Aug 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces lysine with glutamic acid at codon 294 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not impact prodomain cleavage, cellular localization, adhesion and protein binding properties of DSG2 protein (PMID: 23071725, 30885746). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 24070718, 26138720), hypertrophic cardiomyopathy (PMID: 30847666), idiopathic dilated cardiomyopathy (PMID: 34036930), or sudden explained death (PMID: 26272908, 33762593). This variant has also been identified in 6/280794 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. -

Cardiomyopathy

Uncertain:2

Nov 01, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified

Uncertain:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 report, functional study does not predict impact; ExAC: 1/9800 African chromosomes -

Arrhythmogenic right ventricular dysplasia 10

Uncertain:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 294 of the DSG2 protein (p.Lys294Glu). This variant is present in population databases (rs752432726, gnomAD 0.005%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy and/or dilated cardiomyopathy (PMID: 16505173, 24070718, 34036930). ClinVar contains an entry for this variant (Variation ID: 199803). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. Experimental studies have shown that this missense change does not substantially affect DSG2 function (PMID: 23071725, 30885746). 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. -

Cardiovascular phenotype

Uncertain:1

Jul 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K294E variant (also known as c.880A>G), located in coding exon 8 of the DSG2 gene, results from an A to G substitution at nucleotide position 880. The lysine at codon 294 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM) and intrauterine fetal death (Pilichou K et al. Circulation, 2006 Mar;113:1171-9; Muin DA et al. Sci Rep, 2021 Mar;11:6737; Mehaney DA et al. Cardiol Young, 2022 Feb;32:295-300; Stava TT et al. Eur J Prev Cardiol, 2022 Oct;29:1789-1799). The impact on protein function from functional studies is uncertain (Gaertner A et al. PLoS One, 2012 Oct;7:e47097; Debus JD et al. J Mol Cell Cardiol, 2019 Apr;129:303-313). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.77

M_CAP

Benign

0.033

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.82

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.1

REVEL

Benign

0.24

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.025

Polyphen

0.98

Vest4

0.62

MutPred

0.81

Loss of ubiquitination at K294 (P = 0.0326);

MVP

0.83

MPC

0.47

ClinPred

0.42

GERP RS

5.3

Varity_R

0.61

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over