rs79241126

Positions:

chr18-31542655-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 (★★).

Frequency

Genomes: 𝑓 0.053 ( 284 hom., cov: 31)

Exomes 𝑓: 0.069 ( 4023 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 0.591

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:

DSG2-AS1 (HGNC:):

DSG2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.2137G>A	p.Glu713Lys	missense_variant	14/15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 linkuse as main transcript	c.1603G>A	p.Glu535Lys	missense_variant	15/16		XP_047293271.1
DSG2-AS1	NR_045216.1 linkuse as main transcript	n.1811-334C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 linkuse as main transcript	c.2137G>A	p.Glu713Lys	missense_variant	14/15	1	NM_001943.5	ENSP00000261590.8		Q14126
DSG2-AS1	ENST00000583706.5 linkuse as main transcript	n.1849-334C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0531

AC:

8079

AN:

152096

Hom.:

284

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0672

AC XY:

48888

AN XY:

727242

show subpopulations

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.:

AF XY:

0.0533

AC XY:

3964

AN XY:

74414

show subpopulations

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:

ESP6500EA

AF:

0.0777

AC:

652

ExAC

AF:

0.0518

AC:

6264

Asia WGS

AF:

0.00520

AC:

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

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	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	Eurofins Ntd Llc (ga)	Nov 11, 2015	- -
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	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	-	- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2024	- -

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 dysplasia 10

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.1

REVEL

Benign

0.13

Sift

Benign

0.11

Sift4G

Benign

0.19

Polyphen

0.91

Vest4

0.096

MPC

0.12

ClinPred

0.0070

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

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