18-31545820-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001943.5(DSG2):c.2434G>T(p.Gly812Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G812S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:6

Conservation

PhyloP100: 5.53

Publications

22 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 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001943.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	NM_001943.5	MANE Select	c.2434G>T	p.Gly812Cys	missense	Exon 15 of 15	NP_001934.2
	DSG2-AS1	NR_045216.1		n.1432C>A		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DSG2	ENST00000261590.13	TSL:1 MANE Select	c.2434G>T	p.Gly812Cys	missense	Exon 15 of 15	ENSP00000261590.8
DSG2	ENST00000713817.1		c.2425G>T	p.Gly809Cys	missense	Exon 16 of 16	ENSP00000519121.1
DSG2	ENST00000713819.1		c.2425G>T	p.Gly809Cys	missense	Exon 17 of 17	ENSP00000519123.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249442

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1112004

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000119

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

May 30, 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 glycine with cysteine at codon 812 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant does not affect membrane expression of the mutant protein and does not affect cardiomyocyte cohesion in vitro (PMID: 25213555). This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 16773573, 20031617), in an individual affected with probable ARVC (PMID: 20857253) and in an individual affected with exercise-induced ARVC (PMID: 23871885). This variant has been identified in 3/249442 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

Pathogenic:1Uncertain:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 812 of the DSG2 protein (p.Gly812Cys). This variant is present in population databases (rs121913010, gnomAD 0.003%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 16773573). This variant is also known as 2431G>T, G811C. ClinVar contains an entry for this variant (Variation ID: 16814). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on DSG2 function (PMID: 20708101, 25213555). 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.

Jul 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Uncertain:2

Jan 20, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Gly812Cys variant in DSG2 has been identified in at least 2 individuals with ARVC (Awad 2006, Ambry pers. comm., LMM data). It has also been identified in 0.003% (3/113164) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In contrast, in vitro functional studies do not provide strong support for or against an impact to the protein (Gehmlich 2010). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4_Supporting.

Dec 16, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Pathogenic:1

Aug 15, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G812C variant (also known as c.2434G>T), located in coding exon 15 of the DSG2 gene, results from a G to T substitution at nucleotide position 2434. The glycine at codon 812 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple probands with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Awad MM et al. Am. J. Hum. Genet., 2006 Jul;79:136-42; Ambry internal data). Functional studies in vitro have demonstrated normal desmoglein-2 subcellular localization, protein-protein interactions, and cardiomyocyte cohesion; however, the mechanism by which alterations in DSG2 contribute to disease is not completely understood (Gehmlich K et al. Heart Rhythm, 2010 Oct;7:1446-53; Schlipp A et al. Cardiovasc. Res., 2014 Nov;104:245-57). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Cardiomyopathy

Uncertain:1

May 03, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with cysteine at codon 812 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not affect membrane expression of the mutant protein and does not affect cardiomyocyte cohesion in vitro (PMID: 25213555). This variant has been reported in individuals affected with or suspected of having arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 16773573, 20031617, 20857253, 23871885, 25820315). This variant has been identified in 3/249442 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.

DSG2-related disorder

Uncertain:1

Dec 18, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DSG2 c.2434G>T variant is predicted to result in the amino acid substitution p.Gly812Cys. This variant has been reported in two individuals diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) (reported as p.Gly811Cys in Table 1, Awad et al. 2006. PubMed ID: 16773573; Tan et al. 2010. PubMed ID: 20857253). It was also been observed in an individual with suspected ARVC (den Haan et al. 2009. PubMed ID: 20031617) and another individual who experienced ARVC symptoms following strenuous exercise (Table S1, James et al. 2013. PubMed ID: 23871885). In vitro studies using rat cardiomyocytes found p.Gly812Cys-DSG2 had normal protein expression and cell membrane localization (Gehmlich et al. 2010. PubMed ID: 20708101). Additional experiments (same study) demonstrated this variant does not apparently alter plakoglobin binding affinity but were inconclusive regarding its effect on plakophilin-2 binding. Another study performed a cell fragmentation assay using mouse cardiomyocytes and found that the p.Gly812Cys variant did not significantly alter cell-cell adhesion relative to wild type (Schlipp et al. 2014. PubMed ID: 25213555). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.5

PhyloP100

5.5

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MVP

0.97

MPC

0.43

ClinPred

1.0

GERP RS

6.0

Varity_R

0.81

gMVP

0.71

Mutation Taster

=30/70

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over