rs79241126

chr18-31542655-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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. E713D) 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:17
• Conservation: PhyloP100: 0.591

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

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 44295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31542655-G-A is described in Lovd as [Benign]. Variant chr18-31542655-G-A is described in Lovd as [Pathogenic]. Variant chr18-31542655-G-A is described in Lovd as [Likely_pathogenic].
• 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/exons	MANE	UniProt
DSG2	NM_001943.5	c.2137G>A	p.Glu713Lys	missense_variant	14/15	ENST00000261590.13
DSG2-AS1	NR_045216.1	n.1811-334C>T		intron_variant, non_coding_transcript_variant
DSG2	XM_047437315.1	c.1603G>A	p.Glu535Lys	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.2137G>A	p.Glu713Lys	missense_variant	14/15	1	NM_001943.5	P1
DSG2-AS1	ENST00000583706.5	n.1849-334C>T		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.0529 AC: 13204 AN: 249434 Hom.: 499 AF XY: 0.0525 AC XY: 7101 AN XY: 135316

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 SAS exome AF: 0.0131

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

Gnomad4 AFR exome AF: 0.00953

Gnomad4 AMR exome AF: 0.0339

Gnomad4 ASJ exome AF: 0.0606

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.0992

Gnomad4 NFE exome AF: 0.0783

Gnomad4 OTH exome AF: 0.0624

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

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.0419

Gnomad4 ASJ AF: 0.0637

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.0784

Gnomad4 OTH AF: 0.0540

Alfa AF: 0.0692 Hom.: 643

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:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 03, 2011	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. -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 04, 2019	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 08, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

Arrhythmogenic right ventricular cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Arrhythmogenic right ventricular dysplasia 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2015

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
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.11	T
Sift4G	Benign	0.19	T
Polyphen		0.91	P
Vest4		0.096
MPC		0.12
ClinPred		0.0070	T
GERP RS		3.2
Varity_R		0.062
gMVP		0.57

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

Other links and lift over

dbSNP: rs79241126; hg19: chr18-29122618;