rs770921270

Positions:

• chr18-31524748-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM5 PP3_Moderate BS2

The NM_001943.5(DSG2):​c.874C>T​(p.Arg292Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,613,930 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R292L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:2 U:10
• Conservation: PhyloP100: 1.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31524749-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199802.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• BS2: High AC in GnomAdExome4 at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5	c.874C>T	p.Arg292Cys	missense_variant	8/15	ENST00000261590.13
DSG2	XM_047437315.1	c.340C>T	p.Arg114Cys	missense_variant	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.874C>T	p.Arg292Cys	missense_variant	8/15	1	NM_001943.5	P1
DSG2	ENST00000682087.2	n.705C>T		non_coding_transcript_exon_variant	6/6
DSG2	ENST00000683614.2	n.705C>T		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152078 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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: 0.0000481 AC: 12 AN: 249360 Hom.: 0 AF XY: 0.0000591 AC XY: 8 AN XY: 135300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000581 AC: 85 AN: 1461852 Hom.: 0 Cov.: 35 AF XY: 0.0000646 AC XY: 47 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00118

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152078 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74264

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000331 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2021	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: 30454721, 21606396, 28097316, 25820315, 22000064, 22214898, 27532257, 29178656) -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1 Uncertain:2

Pathogenic, no assertion criteria provided	literature only	Cardiac Research Department, West China Second University Hospital	Jan 01, 2011	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 05, 2024	This missense variant replaces arginine with cysteine at codon 292 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in homozygous or heterozygous state in individuals affected with arrhythmogenic right ventricular cardiomyopathy; however, it has also been carried by their unaffected relatives (PMID: 21606396, 22000064, 22214898, 25820315, 27532257, 29178656, 30454721, 32877757). One of the affected individuals also carried a pathogenic PKP2 truncation variant, which could explain the disease observed in that individual (PMID: 22214898). This variant has also been identified in 12/249360 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:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 292 of the DSG2 protein (p.Arg292Cys). This variant is present in population databases (rs770921270, gnomAD 0.02%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606396, 22000064, 22214898, 25820315, 27532257, 29178656, 30454721). ClinVar contains an entry for this variant (Variation ID: 466351). 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%. 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. -
Likely pathogenic, flagged submission	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 13, 2020	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS4_Mod,PM2,PP3,PP4. This variant was detected in homozygous state. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 20, 2023

This missense variant replaces arginine with cysteine at codon 292 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in homozygous or heterozygous state in individuals affected with arrhythmogenic right ventricular cardiomyopathy; however, it has also been carried by their unaffected relatives (PMID: 21606396, 22000064, 22214898, 25820315, 27532257, 29178656, 30454721, 32877757, 36138163). Two of the affected individuals also carried a pathogenic PKP2 variant, which could explain the disease observed in that individual (PMID: 22214898, 36138163). This variant has also been identified in 12/249360 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2020

The p.R292C variant (also known as c.874C>T), located in coding exon 8 of the DSG2 gene, results from a C to T substitution at nucleotide position 874. The arginine at codon 292 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts (Groeneweg JA et al. Circ Cardiovasc Genet, 2015 Jun;8:437-46; Te Riele ASJM et al. JACC Clin Electrophysiol, 2015 Dec;1:551-560; Walsh R et al. Genet. Med., 2017 02;19:192-203). However, in many probands this alteration was detected in the homozygous or compound heterozygous state or co-occurred with alterations in other ARVC-associated genes, and a number of relatives positive for the R292C alteration were reported to be unaffected (Cox MG et al. Circulation, 2011 Jun;123:2690-700; Sato T et al. Leg Med (Tokyo), 2011 Nov;13:298-300; Nakajima T et al. Circ. J., 2012 Dec;76:737-43; Wada Y et al. Mol Genet Genomic Med, 2017 11;5:639-651). 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	Uncertain	0.42
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.57		Loss of sheet (P = 0.0817);
MVP		0.87
MPC		0.49
ClinPred		0.88	D
GERP RS		5.3
Varity_R		0.79
gMVP		0.78

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: rs770921270; hg19: chr18-29104711; COSMIC: COSV55198442; COSMIC: COSV55198442;