rs2278792

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001943.5(DSG2):c.2318G>A(p.Arg773Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,376,676 control chromosomes in the GnomAD database, including 55,785 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 Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4237 hom., cov: 26)

Exomes 𝑓: 0.30 ( 51548 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 1.83

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:51311): (DSG2 antisense RNA 1)

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=0.0026043653).

BP6

Variant 18-31542836-G-A is Benign according to our data. Variant chr18-31542836-G-A is described in ClinVar as [Benign]. Clinvar id is 44300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31542836-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5 link	c.2318G>A	p.Arg773Lys	missense_variant	Exon 14 of 15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 link	c.1784G>A	p.Arg595Lys	missense_variant	Exon 15 of 16		XP_047293271.1
DSG2-AS1	NR_045216.1 link	n.1810+266C>T		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 link	c.2318G>A	p.Arg773Lys	missense_variant	Exon 14 of 15	1	NM_001943.5	ENSP00000261590.8		Q14126
DSG2-AS1	ENST00000583706.5 link	n.1848+266C>T		intron_variant	Intron 5 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

32204

AN:

140046

Hom.:

4233

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0830

Gnomad AMI

AF:

0.161

Gnomad AMR

AF:

0.283

Gnomad ASJ

AF:

0.179

Gnomad EAS

AF:

0.476

Gnomad SAS

AF:

0.262

Gnomad FIN

AF:

0.383

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.267

Gnomad OTH

AF:

0.223

GnomAD3 exomes

AF:

0.265

AC:

53755

AN:

202736

Hom.:

7971

AF XY:

0.264

AC XY:

28946

AN XY:

109800

show subpopulations

Gnomad AFR exome

AF:

0.0722

Gnomad AMR exome

AF:

0.281

Gnomad ASJ exome

AF:

0.169

Gnomad EAS exome

AF:

0.467

Gnomad SAS exome

AF:

0.247

Gnomad FIN exome

AF:

0.335

Gnomad NFE exome

AF:

0.255

Gnomad OTH exome

AF:

0.249

GnomAD4 exome

AF:

0.299

AC:

369845

AN:

1236560

Hom.:

51548

Cov.:

AF XY:

0.298

AC XY:

181338

AN XY:

608972

show subpopulations

Gnomad4 AFR exome

AF:

0.0874

Gnomad4 AMR exome

AF:

0.311

Gnomad4 ASJ exome

AF:

0.233

Gnomad4 EAS exome

AF:

0.559

Gnomad4 SAS exome

AF:

0.245

Gnomad4 FIN exome

AF:

0.395

Gnomad4 NFE exome

AF:

0.296

Gnomad4 OTH exome

AF:

0.309

GnomAD4 genome

AF:

0.230

AC:

32211

AN:

140116

Hom.:

4237

Cov.:

AF XY:

0.238

AC XY:

16033

AN XY:

67414

show subpopulations

Gnomad4 AFR

AF:

0.0830

Gnomad4 AMR

AF:

0.283

Gnomad4 ASJ

AF:

0.179

Gnomad4 EAS

AF:

0.476

Gnomad4 SAS

AF:

0.259

Gnomad4 FIN

AF:

0.383

Gnomad4 NFE

AF:

0.267

Gnomad4 OTH

AF:

0.230

Alfa

AF:

0.253

Hom.:

11524

Bravo

AF:

0.209

TwinsUK

AF:

0.263

AC:

974

ALSPAC

AF:

0.259

AC:

998

ESP6500AA

AF:

0.0778

AC:

307

ESP6500EA

AF:

0.254

AC:

2109

ExAC

AF:

0.259

AC:

31247

Asia WGS

AF:

0.344

AC:

1197

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 07, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

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

- -

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

Significance: Benign

Review Status: no assertion criteria provided

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

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33047533) -

Nov 21, 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: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiomyopathy

Benign:2

Apr 08, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 10

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 11, 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

0.082

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.13

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0026

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.35

REVEL

Benign

0.092

Sift

Benign

0.38

Sift4G

Benign

0.31

Polyphen

0.026

Vest4

0.020

MPC

0.074

ClinPred

0.0055

GERP RS

2.2

Varity_R

0.037

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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