18-31545820-G-T

Position:

chr18-31545820-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM5PP3_StrongBS2

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 Pathogenic.

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

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-31545820-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSG2	NM_001943.5 linkuse as main transcript	c.2434G>T	p.Gly812Cys	missense_variant	15/15	ENST00000261590.13	NP_001934.2
DSG2-AS1	NR_045216.1 linkuse as main transcript	n.1432C>A		non_coding_transcript_exon_variant	4/6
DSG2	XM_047437315.1 linkuse as main transcript	c.1900G>T	p.Gly634Cys	missense_variant	16/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DSG2	ENST00000261590.13 linkuse as main transcript	c.2434G>T	p.Gly812Cys	missense_variant	15/15	1	NM_001943.5	ENSP00000261590	P1
DSG2-AS1	ENST00000583706.5 linkuse as main transcript	n.1470C>A		non_coding_transcript_exon_variant	4/6	5
DSG2-AS1	ENST00000657343.1 linkuse as main transcript	n.783C>A		non_coding_transcript_exon_variant	4/4

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

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249442

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135328

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	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. -
Likely pathogenic, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Arrhythmogenic right ventricular dysplasia 10

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 20, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 16, 2021	- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2018

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). Another alteration affecting this amino acid (p.G812S, c.2434G>A) has been identified in a proband with ARVC and has been reported to co-segregate with disease (Gehmlich K et al. Heart Rhythm, 2010 Oct;7:1446-53). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 18, 2023

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 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. -

DSG2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2023

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

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

MutationTaster

Benign

1.0

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

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

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