rs2230233

Positions:

• chr18-31524735-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001943.5(DSG2):​c.861C>T​(p.Asn287Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 1,613,824 control chromosomes in the GnomAD database, including 135,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (21314 hom., cov: 33)
  • Exomes 𝑓: 0.39 (114189 hom.)
• Consequence: DSG2 NM_001943.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.0120

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 18-31524735-C-T is Benign according to our data. Variant chr18-31524735-C-T is described in ClinVar as [Benign]. Clinvar id is 44329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31524735-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.012 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.861C>T	p.Asn287Asn	synonymous_variant	8/15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.327C>T	p.Asn109Asn	synonymous_variant	9/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.861C>T	p.Asn287Asn	synonymous_variant	8/15	1	NM_001943.5	ENSP00000261590.8
DSG2	ENST00000682087.2	n.692C>T		non_coding_transcript_exon_variant	6/6
DSG2	ENST00000683614.2	n.692C>T		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75613 AN: 151998 Hom.: 21262 Cov.: 33

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.461

GnomAD3 exomes AF: 0.407 AC: 101570 AN: 249298 Hom.: 22483 AF XY: 0.395 AC XY: 53489 AN XY: 135264

Gnomad AFR exome AF: 0.803

Gnomad AMR exome AF: 0.411

Gnomad ASJ exome AF: 0.319

Gnomad EAS exome AF: 0.493

Gnomad SAS exome AF: 0.322

Gnomad FIN exome AF: 0.408

Gnomad NFE exome AF: 0.372

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.387 AC: 566326 AN: 1461708 Hom.: 114189 Cov.: 56 AF XY: 0.383 AC XY: 278745 AN XY: 727166

Gnomad4 AFR exome AF: 0.801

Gnomad4 AMR exome AF: 0.413

Gnomad4 ASJ exome AF: 0.319

Gnomad4 EAS exome AF: 0.521

Gnomad4 SAS exome AF: 0.322

Gnomad4 FIN exome AF: 0.404

Gnomad4 NFE exome AF: 0.374

Gnomad4 OTH exome AF: 0.406

GnomAD4 genome AF: 0.498 AC: 75726 AN: 152116 Hom.: 21314 Cov.: 33 AF XY: 0.495 AC XY: 36797 AN XY: 74356

Gnomad4 AFR AF: 0.785

Gnomad4 AMR AF: 0.426

Gnomad4 ASJ AF: 0.330

Gnomad4 EAS AF: 0.503

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.405

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.466

Alfa AF: 0.398 Hom.: 16771

Bravo AF: 0.513

Asia WGS AF: 0.507 AC: 1766 AN: 3478

EpiCase AF: 0.370

EpiControl AF: 0.363

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cardiomyopathy Benign:2

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

Arrhythmogenic right ventricular dysplasia 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 02, 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	-0.55
CADD	Benign	3.4
DANN	Benign	0.41

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: rs2230233; hg19: chr18-29104698; COSMIC: COSV55199580; COSMIC: COSV55199580;