rs1042769

Positions:

• chr18-31545891-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001943.5(DSG2):​c.2505A>G​(p.Thr835=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,613,976 control chromosomes in the GnomAD database, including 13,505 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T835T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (3247 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10258 hom.)
• Consequence: DSG2 NM_001943.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -2.77

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 18-31545891-A-G is Benign according to our data. Variant chr18-31545891-A-G is described in ClinVar as [Benign]. Clinvar id is 44302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31545891-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5	c.2505A>G	p.Thr835=	synonymous_variant	15/15	ENST00000261590.13
DSG2-AS1	NR_045216.1	n.1361T>C		non_coding_transcript_exon_variant	4/6
DSG2	XM_047437315.1	c.1971A>G	p.Thr657=	synonymous_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.2505A>G	p.Thr835=	synonymous_variant	15/15	1	NM_001943.5	P1
DSG2-AS1	ENST00000583706.5	n.1399T>C		non_coding_transcript_exon_variant	4/6	5
DSG2-AS1	ENST00000657343.1	n.712T>C		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26974 AN: 151986 Hom.: 3236 Cov.: 32

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.0903

Gnomad FIN AF: 0.0598

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.164

GnomAD3 exomes AF: 0.125 AC: 31107 AN: 249234 Hom.: 2543 AF XY: 0.120 AC XY: 16174 AN XY: 135236

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.197

Gnomad SAS exome AF: 0.0723

Gnomad FIN exome AF: 0.0722

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.110 AC: 160751 AN: 1461874 Hom.: 10258 Cov.: 32 AF XY: 0.108 AC XY: 78724 AN XY: 727242

Gnomad4 AFR exome AF: 0.351

Gnomad4 AMR exome AF: 0.129

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.201

Gnomad4 SAS exome AF: 0.0753

Gnomad4 FIN exome AF: 0.0707

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.178 AC: 27023 AN: 152102 Hom.: 3247 Cov.: 32 AF XY: 0.174 AC XY: 12923 AN XY: 74358

Gnomad4 AFR AF: 0.344

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.208

Gnomad4 SAS AF: 0.0906

Gnomad4 FIN AF: 0.0598

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.164

Alfa AF: 0.127 Hom.: 1968

Bravo AF: 0.191

Asia WGS AF: 0.185 AC: 644 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2007	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 08, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

Arrhythmogenic right ventricular dysplasia 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.17
DANN	Benign	0.71

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: rs1042769; hg19: chr18-29125854; COSMIC: COSV55200374; COSMIC: COSV55200374;