rs2230234

Variant summary

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

The NM_001943.5(DSG2):c.877A>G(p.Ile293Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.078 in 1,614,152 control chromosomes in the GnomAD database, including 5,572 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I293L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.065 ( 476 hom., cov: 33)

Exomes 𝑓: 0.079 ( 5096 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 2.20

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026659071).

BP6

Variant 18-31524751-A-G is Benign according to our data. Variant chr18-31524751-A-G is described in ClinVar as [Benign]. Clinvar id is 44331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31524751-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.877A>G	p.Ile293Val	missense_variant	8/15	ENST00000261590.13
DSG2	XM_047437315.1 linkuse as main transcript	c.343A>G	p.Ile115Val	missense_variant	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DSG2	ENST00000261590.13 linkuse as main transcript	c.877A>G	p.Ile293Val	missense_variant	8/15	1	NM_001943.5	P1
DSG2	ENST00000682087.2 linkuse as main transcript	n.708A>G		non_coding_transcript_exon_variant	6/6
DSG2	ENST00000683614.2 linkuse as main transcript	n.708A>G		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes

AF:

0.0646

AC:

9832

AN:

152196

Hom.:

476

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.206

Gnomad AMR

AF:

0.0489

Gnomad ASJ

AF:

0.0790

Gnomad EAS

AF:

0.000961

Gnomad SAS

AF:

0.0412

Gnomad FIN

AF:

0.152

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0884

Gnomad OTH

AF:

0.0627

GnomAD3 exomes

AF:

0.0687

AC:

17121

AN:

249370

Hom.:

793

AF XY:

0.0705

AC XY:

9534

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.0395

Gnomad ASJ exome

AF:

0.0770

Gnomad EAS exome

AF:

0.000278

Gnomad SAS exome

AF:

0.0443

Gnomad FIN exome

AF:

0.145

Gnomad NFE exome

AF:

0.0865

Gnomad OTH exome

AF:

0.0838

GnomAD4 exome

AF:

0.0794

AC:

116110

AN:

1461838

Hom.:

5096

Cov.:

AF XY:

0.0791

AC XY:

57542

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0134

Gnomad4 AMR exome

AF:

0.0418

Gnomad4 ASJ exome

AF:

0.0778

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.0452

Gnomad4 FIN exome

AF:

0.141

Gnomad4 NFE exome

AF:

0.0857

Gnomad4 OTH exome

AF:

0.0742

GnomAD4 genome

AF:

0.0645

AC:

9831

AN:

152314

Hom.:

476

Cov.:

AF XY:

0.0665

AC XY:

4954

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0153

Gnomad4 AMR

AF:

0.0489

Gnomad4 ASJ

AF:

0.0790

Gnomad4 EAS

AF:

0.000963

Gnomad4 SAS

AF:

0.0417

Gnomad4 FIN

AF:

0.152

Gnomad4 NFE

AF:

0.0885

Gnomad4 OTH

AF:

0.0621

Alfa

AF:

0.0792

Hom.:

1294

Bravo

AF:

0.0552

TwinsUK

AF:

0.0852

AC:

316

ALSPAC

AF:

0.0885

AC:

341

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.0859

AC:

706

ExAC

AF:

0.0686

AC:

8291

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0848

EpiControl

AF:

0.0859

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 04, 2008	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	This variant is associated with the following publications: (PMID: 33232181, 30716529, 27884173, 18678517, 27153395, 19863551, 16025435, 21397041, 24125834) -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 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

0.22

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.56

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

MutationTaster

Benign

0.073

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.87

REVEL

Benign

0.089

Sift

Uncertain

0.025

Sift4G

Uncertain

0.053

Polyphen

0.99

Vest4

0.15

MPC

0.29

ClinPred

0.031

GERP RS

5.3

Varity_R

0.29

gMVP

0.38

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