NM_001943.5:c.3040G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001943.5(DSG2):c.3040G>A(p.Val1014Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 3.50

Publications

5 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DSG2	NM_001943.5 link	c.3040G>A	p.Val1014Ile	missense_variant	Exon 15 of 15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1 link	c.2506G>A	p.Val836Ile	missense_variant	Exon 16 of 16		XP_047293271.1
DSG2-AS1	NR_045216.1 link	n.1346-520C>T		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 link	c.3040G>A	p.Val1014Ile	missense_variant	Exon 15 of 15	1	NM_001943.5	ENSP00000261590.8

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000722

AC:

AN:

249392

AF XY:

0.0000665

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000175

AC:

256

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

123

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000217

AC:

241

AN:

1112000

Other (OTH)

AF:

0.0000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000920

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000145

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000359

AC:

ExAC

AF:

0.0000496

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Apr 10, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DSG2 c.3040G>A (p.Val1014Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 249792 control chromosomes. The observed variant frequency is approximately 7.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 (1e-05), strongly suggesting that the variant is benign. c.3040G>A has been reported in the literature as a VUS in settings of multigene panel testing of individuals with a variety of cardiac phenotypes such as idiopathic dilated cardiomyopathy (DCM), DCM, exertion-related sudden unexplained death in the young (SUDY) (example, Elliott_2010, Pugh_2014, Anderson_2016, Mellor_2017, Walsh_2017) and as a Likely Pathogenic cardiomyopathy associated variant in at-least one individual with hypertension/stroke (example, Ng_2013). These data do not allow any conclusion about variant significance. At-least one of these reports mentions a co-occurrence with another pathogenic variant in an individual with exertion-related sudden unexplained death in the young (SUDY) (MYBPC3 c.2374T>C, p.Trp792Arg), providing supporting evidence for a benign role (Anderson_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; Likely benign, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Jul 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Val1014Ile variant in DSG2 has been reported in 1 individual with DCM and wa s absent from 400 control chromosomes (Elliott 2010). In addition, this variant has been identified in 3/8352 European American chromosomes from a broad populat ion by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). C omputational analyses (biochemical amino acid properties, conservation, AlignGVG D, PolyPhen2, and SIFT) do not provide strong support for or against an impact t o the protein. Additional information is needed to fully assess the clinical sig nificance of the Val1014Ile variant. -

Cardiomyopathy

Uncertain:1Benign:1

Dec 18, 2015

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 19, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces valine with isoleucine at codon 1014 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been identified in three individuals affected with dilated cardiomyopathy (PMID: 20716751, 23861362, 24503780). This variant has been observed in a young individual with exertion-induced sudden unexplained death, who also carried a pathogenic variant in the MYBPC3 gene (PMID: 27114410). This variant has also been identified in 19/280798 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Arrhythmogenic right ventricular dysplasia 10

Uncertain:1

Jan 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1014 of the DSG2 protein (p.Val1014Ile). This variant is present in population databases (rs200830807, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 20716751, 23861362, 24503780, 27532257). ClinVar contains an entry for this variant (Variation ID: 44309). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Primary dilated cardiomyopathy

Uncertain:1

Apr 05, 2018

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Cardiovascular phenotype

Uncertain:1

Mar 25, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3040G>A (p.V1014I) alteration is located in exon 15 (coding exon 15) of the DSG2 gene. This alteration results from a G to A substitution at nucleotide position 3040, causing the valine (V) at amino acid position 1014 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Mar 26, 2025

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.61

M_CAP

Benign

0.073

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.0

PhyloP100

3.5

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.52

REVEL

Uncertain

0.30

Sift

Benign

0.045

Sift4G

Pathogenic

0.0

Polyphen

0.80

Vest4

0.68

MVP

0.73

MPC

0.24

ClinPred

0.11

GERP RS

4.3

Varity_R

0.034

gMVP

0.33

Mutation Taster

=25/75

disease causing

(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