rs121913010

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001943.5(DSG2):c.2434G>A(p.Gly812Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000366 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G812C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9

Conservation

PhyloP100: 5.53

Publications

22 publications found

Variant links:

COSMIC-nc: COSV106407886

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.

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>A	p.Gly812Ser	missense	Exon 15 of 15	NP_001934.2
	DSG2-AS1	NR_045216.1		n.1432C>T		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>A	p.Gly812Ser	missense	Exon 15 of 15	ENSP00000261590.8
DSG2	ENST00000713817.1		c.2425G>A	p.Gly809Ser	missense	Exon 16 of 16	ENSP00000519121.1
DSG2	ENST00000713819.1		c.2425G>A	p.Gly809Ser	missense	Exon 17 of 17	ENSP00000519123.1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000735

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000241

AC:

AN:

249442

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000447

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:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000261

AC:

AN:

1112004

Other (OTH)

AF:

0.0000993

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.0000854

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41418

American (AMR)

AF:

0.000393

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:

0.0000735

AC:

AN:

68038

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.0000356

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 27, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30615648, 25213555, 23911551, 27532257, 28567303, 26633542, 20708101, 28454995, 30847666, 32516855, 31402444)

Cardiomyopathy

Uncertain:2

Oct 19, 2021

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 03, 2025

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 serine at codon 812 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function. An experimental study has suggested that this variant does not cause significant loss of cell-cell cohesion in vitro (PMID: 25213555). This variant has been identified in four individuals affected with arrhythmogenic right ventricular cardiomyopathy in one family and was absent in five unaffected family members (PMID: 20708101). This variant has been reported in another six individuals affected with or suspected to be affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257, 28454995, 28567303, 32114801, 36621286); in an individual affected with left ventricular noncompaction cardiomyopathy after pericarditis (PMID: 32516855); in an individual with unspecified cardiomyopathy (PMID: 30847666); and in a few exome-sequencing participants not selected for cardiomyopathy phenotype (PMID: 24055113, 26633542). This variant has also been identified in 11/280834 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 cardiomyopathy

Uncertain:1

Sep 23, 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 serine at codon 812 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). An experimental study has suggested that this variant does not cause significant loss of cell-cell cohesion in vitro (PMID: 25213555). This variant has been identified in four individuals affected with arrhythmogenic right ventricular cardiomyopathy in one family and absent in five unaffected family members (PMID: 20708101). This variant has been reported in another six individuals affected with or suspected of having arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257, 28454995, 28567303, 32114801, 36621286), in an individual affected with left ventricular noncompaction cardiomyopathy after pericarditis (PMID: 32516855), in an individual with unspecified cardiomyopathy (PMID: 30847666), and in a few exome-sequencing participants not selected for cardiomyopathy phenotype (PMID: 24055113, 26633542). This variant has also been identified in 11/280834 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 20, 2025

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 serine, which is neutral and polar, at codon 812 of the DSG2 protein (p.Gly812Ser). This variant is present in population databases (rs121913010, gnomAD 0.009%). This missense change has been observed in individual(s) with DSG2-related conditions (PMID: 20031617, 20708101, 27532257, 28454995, 30847666, 32516855). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199817). 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) indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on DSG2 function (PMID: 20708101, 25213555). This variant disrupts the p.Gly812 amino acid residue in DSG2. Other variant(s) that disrupt this residue have been observed in individuals with DSG2-related conditions (PMID: 16773573), which suggests that this may be a clinically significant amino acid residue. 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.

Hypertrophic cardiomyopathy

Uncertain:1

Dec 12, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG: BS2

Cardiovascular phenotype

Uncertain:1

Dec 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G812S variant (also known as c.2434G>A), located in coding exon 15 of the DSG2 gene, results from a G to A substitution at nucleotide position 2434. The glycine at codon 812 is replaced by serine, an amino acid with similar properties. This alteration has been reported in individuals with features consistent with arrhythmogenic right ventricular cardiomyopathy (ARVC), but has also been detected in individuals without significant ARVC findings (Gehmlich K et al. Heart Rhythm, 2010 Oct;7:1446-53; Retterer K et al. Genet. Med., 2016 07;18:696-704; Stavropoulos DJ et al. NPJ Genom Med, 2016 Jan;1; Walsh R et al. Genet. Med., 2017 02;19:192-203;pers. comm.; Ambry internal data). This alteration was reported to segregate with disease in a family with ARVC; however, one young relative with a borderline ARVC diagnosis was negative for this variant (Gehmlich K et al, Heart Rhythm 2010 Oct; 7(10):1446-53). In vitro functional studies have not detected a negative impact on DSG2 function; however, these studies may not reflect in vivo function (Gehmlich K et al, Heart Rhythm 2010 Oct; 7(10):1446-53; Schlipp A et al. Cardiovasc. Res., 2014 Nov;104:245-5). 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 available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.3

PhyloP100

5.5

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.47

Sift

Benign

0.039

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.39

MutPred

0.72

Gain of disorder (P = 0.0626)

MVP

0.85

MPC

0.42

ClinPred

0.97

GERP RS

6.0

Varity_R

0.43

gMVP

0.67

Mutation Taster

=20/80

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over