rs2230233

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001943.5(DSG2):c.861C>T(p.Asn287=) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.0120

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.861C>T	p.Asn287=	synonymous_variant	8/15	ENST00000261590.13
DSG2	XM_047437315.1 linkuse as main transcript	c.327C>T	p.Asn109=	synonymous_variant	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DSG2	ENST00000261590.13 linkuse as main transcript	c.861C>T	p.Asn287=	synonymous_variant	8/15	1	NM_001943.5	P1
DSG2	ENST00000682087.2 linkuse as main transcript	n.692C>T		non_coding_transcript_exon_variant	6/6
DSG2	ENST00000683614.2 linkuse as main transcript	n.692C>T		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes

AF:

0.497

AC:

75613

AN:

151998

Hom.:

21262

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.383

AC XY:

278745

AN XY:

727166

show subpopulations

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.:

AF XY:

0.495

AC XY:

36797

AN XY:

74356

show subpopulations

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:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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	Invitae	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. -

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over