chr18-31545820-G-A

Position:

chr18-31545820-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM5BS2

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 Pathogenic.

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:8

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 Likely_benign. Variant got -2 ACMG points.

PM5

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

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSG2	NM_001943.5 linkuse as main transcript	c.2434G>A	p.Gly812Ser	missense_variant	15/15	ENST00000261590.13	NP_001934.2
DSG2-AS1	NR_045216.1 linkuse as main transcript	n.1432C>T		non_coding_transcript_exon_variant	4/6
DSG2	XM_047437315.1 linkuse as main transcript	c.1900G>A	p.Gly634Ser	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>A	p.Gly812Ser	missense_variant	15/15	1	NM_001943.5	ENSP00000261590	P1
DSG2-AS1	ENST00000583706.5 linkuse as main transcript	n.1470C>T		non_coding_transcript_exon_variant	4/6	5
DSG2-AS1	ENST00000657343.1 linkuse as main transcript	n.783C>T		non_coding_transcript_exon_variant	4/4

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

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

249442

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135328

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000261

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000494

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:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2020	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 03, 2023	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 cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

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). 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%. 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2022

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 several arrhythmogenic right ventricular cardiomyopathy (ARVC) patients and in a stillbirth cohort, but it has also been detected in multiple 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; Sahlin E et al. PLoS ONE, 2019 Jan;14:e0210017; Ambry internal data; GeneDx pers. comm.; Invitae pers. comm.). This alteration was reported to segregate with disease in four individuals from a single 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

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

MutationTaster

Benign

1.0

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

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

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