18-31545891-A-G

Position:

chr18-31545891-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001943.5(DSG2):c.2505A>G(p.Thr835Thr) 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 (★★).

Frequency

Genomes: 𝑓 0.18 ( 3247 hom., cov: 32)

Exomes 𝑓: 0.11 ( 10258 hom. )

Consequence

DSG2
NM_001943.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -2.77

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:

DSG2-AS1 (HGNC:):

DSG2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.2505A>G	p.Thr835Thr	synonymous_variant	15/15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 linkuse as main transcript	c.1971A>G	p.Thr657Thr	synonymous_variant	16/16		XP_047293271.1
DSG2-AS1	NR_045216.1 linkuse as main transcript	n.1361T>C		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSG2	ENST00000261590.13 linkuse as main transcript	c.2505A>G	p.Thr835Thr	synonymous_variant	15/15	1	NM_001943.5	ENSP00000261590.8	Q14126
DSG2-AS1	ENST00000583706.5 linkuse as main transcript	n.1399T>C		non_coding_transcript_exon_variant	4/6	5
DSG2-AS1	ENST00000657343.1 linkuse as main transcript	n.712T>C		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26974

AN:

151986

Hom.:

3236

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.108

AC XY:

78724

AN XY:

727242

show subpopulations

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.:

AF XY:

0.174

AC XY:

12923

AN XY:

74358

show subpopulations

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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