rs79241126

Variant names:

• chr18-31542655-G-A
• rs79241126
• NM_001943.5:c.2137G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001943.5(DSG2):​c.2137G>A​(p.Glu713Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0674 in 1,614,098 control chromosomes in the GnomAD database, including 4,307 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E713A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.053 (284 hom., cov: 31)
  • Exomes 𝑓: 0.069 (4023 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.591
• Publications: 14 publications found

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-AS1 (HGNC:51311): (DSG2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019516647).
• BP6: Variant 18-31542655-G-A is Benign according to our data. Variant chr18-31542655-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5	c.2137G>A	p.Glu713Lys	missense_variant	Exon 14 of 15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.1603G>A	p.Glu535Lys	missense_variant	Exon 15 of 16		XP_047293271.1
DSG2-AS1	NR_045216.1	n.1811-334C>T		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.2137G>A	p.Glu713Lys	missense_variant	Exon 14 of 15	1	NM_001943.5	ENSP00000261590.8

Frequencies

GnomAD3 genomes AF: 0.0531 AC: 8079 AN: 152096 Hom.: 284 Cov.: 31

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0784

Gnomad OTH AF: 0.0551

GnomAD2 exomes AF: 0.0529 AC: 13204 AN: 249434 AF XY: 0.0525

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.0310

Gnomad ASJ exome AF: 0.0578

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0982

Gnomad NFE exome AF: 0.0750

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0689 AC: 100729 AN: 1461884 Hom.: 4023 Cov.: 31 AF XY: 0.0672 AC XY: 48888 AN XY: 727242

African (AFR) AF: 0.00953 AC: 319 AN: 33480

American (AMR) AF: 0.0339 AC: 1518 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0606 AC: 1585 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0134 AC: 1156 AN: 86258

European-Finnish (FIN) AF: 0.0992 AC: 5299 AN: 53418

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5768

European-Non Finnish (NFE) AF: 0.0783 AC: 87021 AN: 1112006

Other (OTH) AF: 0.0624 AC: 3767 AN: 60396

GnomAD4 genome AF: 0.0531 AC: 8078 AN: 152214 Hom.: 284 Cov.: 31 AF XY: 0.0533 AC XY: 3964 AN XY: 74414

African (AFR) AF: 0.0131 AC: 545 AN: 41544

American (AMR) AF: 0.0419 AC: 640 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4826

European-Finnish (FIN) AF: 0.102 AC: 1079 AN: 10592

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0784 AC: 5333 AN: 68004

Other (OTH) AF: 0.0540 AC: 114 AN: 2110

Alfa AF: 0.0653 Hom.: 823

Bravo AF: 0.0475

TwinsUK AF: 0.0696 AC: 258

ALSPAC AF: 0.0708 AC: 273

ESP6500AA AF: 0.0180 AC: 72

ESP6500EA AF: 0.0777 AC: 652

ExAC AF: 0.0518 AC: 6264

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0698

EpiControl AF: 0.0708

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 04, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 03, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Glu713Lys variant in DSG2 is a common variant with allele frequencies rangin g from 2-8% in various control cohorts (dbSNP-rs7924116, Biedermann 2005, Basso 2006, Posche 2008, Milting 2008, Drudge 2008, Kauke 2010). At this frequency thi s variant is highly unlikley to cause disease when present in isoaltion but a mo difying role cannot be excluded. Please note that it has also been referred to i n the literature as Glu712Lys.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 11, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 22, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Cardiomyopathy Benign:2

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 08, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arrhythmogenic right ventricular cardiomyopathy Benign:2

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Arrhythmogenic right ventricular dysplasia 10 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

not provided Benign:2

Nov 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Cardiovascular phenotype Benign:1

Jun 23, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.59
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.11	T
Sift4G	Benign	0.19	T
Vest4		0.096
ClinPred		0.0070	T
GERP RS		3.2
Varity_R		0.062
gMVP		0.57
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs79241126; hg19: chr18-29122618; COSMIC: COSV107226276;