18-31524754-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001943.5(DSG2):c.880A>G(p.Lys294Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,614,090 control chromosomes in the GnomAD database, including 2 homozygotes. 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. K294I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (2 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:10
• Conservation: PhyloP100: 4.20

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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5	c.880A>G	p.Lys294Glu	missense_variant	8/15	ENST00000261590.13
DSG2	XM_047437315.1	c.346A>G	p.Lys116Glu	missense_variant	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.880A>G	p.Lys294Glu	missense_variant	8/15	1	NM_001943.5	P1
DSG2	ENST00000682087.2	n.711A>G		non_coding_transcript_exon_variant	6/6
DSG2	ENST00000683614.2	n.711A>G		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249384 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135314

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: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461868 Hom.: 2 Cov.: 35 AF XY: 0.0000454 AC XY: 33 AN XY: 727234

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000248 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 27, 2018	The DSG2 c.880A>G; p.Lys294Glu variant (rs752432726; ClinVar ID 199803) has been reported in a single individual with arrhythmogenic right ventricular cardiomyopathy (Pilichou 2006); however, functional studies of this variant found no defects in prodomain cleavage, adhesion properties, or cellular localization compared to the wild-type protein (Gaertner 2012). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.002% (identified on 6 out of 277,042 chromosomes). The lysine at position 294 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Lys294Glu variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Lys294Glu variant cannot be determined with certainty. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 10, 2020	- -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces lysine with glutamic acid at codon 294 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). A functional study has shown that this variant does not impact prodomain cleavage, cellular localization, adhesion and protein binding properties of DSG2 protein (PMID: 23071725, 30885746). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 24070718, 26138720), hypertrophic cardiomyopathy (PMID: 30847666), idiopathic dilated cardiomyopathy (PMID: 34036930), or sudden explained death (PMID: 26272908, 33762593). This variant has also been identified in 6/280794 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, flagged submission	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2023	This missense variant replaces lysine with glutamic acid at codon 294 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). A functional study has shown that this variant does not impact prodomain cleavage, cellular localization, adhesion and protein binding properties of DSG2 protein (PMID: 23071725, 30885746). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 24070718, 26138720), hypertrophic cardiomyopathy (PMID: 30847666), idiopathic dilated cardiomyopathy (PMID: 34036930), or sudden explained death (PMID: 26272908, 33762593). This variant has also been identified in 6/280794 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 report, functional study does not predict impact; ExAC: 1/9800 African chromosomes -

Arrhythmogenic right ventricular dysplasia 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 14, 2023

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 294 of the DSG2 protein (p.Lys294Glu). This variant is present in population databases (rs752432726, gnomAD 0.005%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy and/or dilated cardiomyopathy (PMID: 16505173, 24070718, 34036930). ClinVar contains an entry for this variant (Variation ID: 199803). 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. Experimental studies have shown that this missense change does not substantially affect DSG2 function (PMID: 23071725, 30885746). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.92	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.24
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.025	D
Polyphen		0.98	D
Vest4		0.62
MutPred		0.81		Loss of ubiquitination at K294 (P = 0.0326);
MVP		0.83
MPC		0.47
ClinPred		0.42	T
GERP RS		5.3
Varity_R		0.61
gMVP		0.74

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: rs752432726; hg19: chr18-29104717;