rs121913010

Positions:

• chr18-31545820-G-A
• chr18-31545820-G-C
• chr18-31545820-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM5 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8
• Conservation: PhyloP100: 5.53

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-AS1 (HGNC:51311): (DSG2 antisense RNA 1)

ACMG classification

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	UniProt
DSG2	NM_001943.5	c.2434G>A	p.Gly812Ser	missense_variant	15/15	ENST00000261590.13	NP_001934.2
DSG2-AS1	NR_045216.1	n.1432C>T		non_coding_transcript_exon_variant	4/6
DSG2	XM_047437315.1	c.1900G>A	p.Gly634Ser	missense_variant	16/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.2434G>A	p.Gly812Ser	missense_variant	15/15	1	NM_001943.5	ENSP00000261590	P1
DSG2-AS1	ENST00000583706.5	n.1470C>T		non_coding_transcript_exon_variant	4/6	5
DSG2-AS1	ENST00000657343.1	n.783C>T		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152142 Hom.: 0 Cov.: 32

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: 6 AN: 249442 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135328

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: 46 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 727236

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: 13 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74316

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.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain: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	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.47
Sift	Benign	0.039	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.72		Gain of disorder (P = 0.0626);
MVP		0.85
MPC		0.42
ClinPred		0.97	D
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

Other links and lift over

dbSNP: rs121913010; hg19: chr18-29125783;