NM_001943.5:c.877A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. 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:19

Conservation

PhyloP100: 2.20

Publications

41 publications found

Variant links:

COSMIC-nc: COSV107226301

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 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
arrhythmogenic right ventricular dysplasia 10
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy 1BB
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

DSG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 44331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5 link	c.877A>G	p.Ile293Val	missense_variant	Exon 8 of 15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 link	c.343A>G	p.Ile115Val	missense_variant	Exon 9 of 16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 link	c.877A>G	p.Ile293Val	missense_variant	Exon 8 of 15	1	NM_001943.5	ENSP00000261590.8		Q14126

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

GnomAD2 exomes

AF:

0.0687

AC:

17121

AN:

249370

AF XY:

0.0705

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 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

African (AFR)

AF:

0.0134

AC:

447

AN:

33480

American (AMR)

AF:

0.0418

AC:

1870

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0778

AC:

2033

AN:

26134

East Asian (EAS)

AF:

0.000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.0452

AC:

3903

AN:

86256

European-Finnish (FIN)

AF:

0.141

AC:

7553

AN:

53420

Middle Eastern (MID)

AF:

0.0912

AC:

526

AN:

5766

European-Non Finnish (NFE)

AF:

0.0857

AC:

95289

AN:

1111978

Other (OTH)

AF:

0.0742

AC:

4479

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

6087

12173

18260

24346

30433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3372

6744

10116

13488

16860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0645

AC:

9831

AN:

152314

Hom.:

476

Cov.:

AF XY:

0.0665

AC XY:

4954

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0153

AC:

636

AN:

41574

American (AMR)

AF:

0.0489

AC:

748

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0790

AC:

274

AN:

3470

East Asian (EAS)

AF:

0.000963

AC:

AN:

5192

South Asian (SAS)

AF:

0.0417

AC:

201

AN:

4824

European-Finnish (FIN)

AF:

0.152

AC:

1609

AN:

10614

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0885

AC:

6017

AN:

68020

Other (OTH)

AF:

0.0621

AC:

131

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

458

917

1375

1834

2292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0773

Hom.:

1793

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:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

Jan 04, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 33232181, 30716529, 27884173, 18678517, 27153395, 19863551, 16025435, 21397041, 24125834) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 27, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Feb 05, 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

Jun 21, 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

0.22

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

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

PhyloP100

2.2

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

Mutation Taster

=84/16

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over