chr18-31546145-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001943.5(DSG2):c.2759T>G(p.Val920Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,614,176 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 26 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:20

Conservation

PhyloP100: 0.145

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:51311): (DSG2 antisense RNA 1)

DSG2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004273176).

BP6

Variant 18-31546145-T-G is Benign according to our data. Variant chr18-31546145-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 44307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31546145-T-G is described in Lovd as [Pathogenic]. Variant chr18-31546145-T-G is described in Lovd as [Benign]. Variant chr18-31546145-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00429 (653/152286) while in subpopulation AMR AF= 0.0101 (155/15304). AF 95% confidence interval is 0.00883. There are 4 homozygotes in gnomad4. There are 313 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 653 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5 link	c.2759T>G	p.Val920Gly	missense_variant	Exon 15 of 15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 link	c.2225T>G	p.Val742Gly	missense_variant	Exon 16 of 16		XP_047293271.1
DSG2-AS1	NR_045216.1 link	n.1346-239A>C		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSG2	ENST00000261590.13 link	c.2759T>G	p.Val920Gly	missense_variant	Exon 15 of 15	1	NM_001943.5	ENSP00000261590.8	Q14126
DSG2-AS1	ENST00000583706.5 link	n.1384-239A>C		intron_variant	Intron 3 of 5	5
DSG2-AS1	ENST00000657343.1 link	n.697-239A>C		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.00430

AC:

654

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00519

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00368

AC:

918

AN:

249158

Hom.:

AF XY:

0.00365

AC XY:

493

AN XY:

135176

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.00547

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00480

Gnomad OTH exome

AF:

0.00380

GnomAD4 exome

AF:

0.00524

AC:

7662

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00503

AC XY:

3661

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.00613

Gnomad4 ASJ exome

AF:

0.0139

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.000262

Gnomad4 NFE exome

AF:

0.00597

Gnomad4 OTH exome

AF:

0.00490

GnomAD4 genome

AF:

0.00429

AC:

653

AN:

152286

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

313

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00518

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00518

Hom.:

Bravo

AF:

0.00467

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00154

AC:

ESP6500EA

AF:

0.00496

AC:

ExAC

AF:

0.00322

AC:

389

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00611

EpiControl

AF:

0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:7

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2015	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 24, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We consider this variant to be of uncertain significance, likely benign, given it is present in multiple control samples and that it failed to segregate with disease in one family. This variant has been reported in 6 unrelated cases with either ARVC or DCM and as many as 6 total cases. Syrris et al (2006) initially identified the variant in a 17 yo male who had a sudden cardiac arrest, a left ventricular variant of ARVC was confirmed on autopsy. The proband’s father who had a positive phenotype on MRI and an abnormal signal average ECG was found to be genotype positive for the variant. Posch et al (2008) identified the variant in two families with dilated cardiomyopathy (note they refer to the variant as p.Val919Gly due to a numbering difference). However they report that the variant did not segregate with the phenotype in one family. In that family five affected relatives had the variant but one affected relative did not, indicating that it is likely not the primary causative variant of their disease. Christensen et al (2010) also reported the variant in 1 case that was clinically borderline for ARVC. Quarta et al (2011) found p.Val920Gly in 2 out of 100 families with ARVC. This is a conservative amino acid change with a nonpolar Valine replaced by a nonpolar Glyceine. SIFT predicts the amino acid change to be tolerated while PolyPhen predicts it to be probably damaging to the resulting protein. A variant in a nearby codon (p.Pro925Ser) has been reported in association with disease (University Medical Center Groningen ARVD/C Genetic Variants Database). Syrris et al (2006) reported that the variant was absent in 200 presumably healthy controls. Posch et al (2008) identified p.Val920Gly in 2 out of 432 presumably healthy control individuals. Christensen et al (2010) reported that the variant was present in 3 out of 650 individuals from a control population. Cox et al (2011) reported that the variant was absent in 200 controls. The variant is listed in dbSNP (rs142841727) with frequency data from the ClinSeq project, where it was seen in 8 of 660 individuals. It is listed in 1000Genomes, but only in reference to the dbSNP entry (as of April 17th, 2013). Additionally the variant was found in 41/4135 Caucasians and 6/1948 African American individuals in the NHLBI Exome Sequencing Project dataset (as of April 17th, 2013). -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 23, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 21, 2015	p.Val920Gly in exon 15 of DSG2: This variant has been reported in several indivi duals with ARVC or DCM but did not segregate with disease in one family member ( Syrris 2007, Posch 2008, Barahona-Dussault 2010, Christensen 2010). It has been identified in 0.5% (316/66608) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142841727). This freq uency strongly argues against a disease causing role but is too low to establish this with confidence. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 04, 2015	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2025	DSG2: BP4, BS2 -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 19, 2015	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 08, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 03, 2020	- -

Arrhythmogenic right ventricular dysplasia 10

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2025	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Arrhythmogenic right ventricular cardiomyopathy;C0878544:Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 02, 2018

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2017

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. -

DSG2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.21

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0043

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.52

Sift

Benign

0.040

Sift4G

Benign

0.23

Polyphen

0.67

Vest4

0.21

MVP

0.59

MPC

0.31

ClinPred

0.016

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.069

gMVP

0.26

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