18-31519887-G-A

Position:

chr18-31519887-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001943.5(DSG2):c.166G>A(p.Val56Met) variant causes a missense change. The variant allele was found at a frequency of 0.00244 in 1,614,130 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 8 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:20O:1

Conservation

PhyloP100: 6.62

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11316037).

BP6

Variant 18-31519887-G-A is Benign according to our data. Variant chr18-31519887-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16818.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=14, Benign=1, Uncertain_significance=3}. Variant chr18-31519887-G-A is described in Lovd as [Benign]. Variant chr18-31519887-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00179 (273/152258) while in subpopulation NFE AF= 0.00316 (215/68020). AF 95% confidence interval is 0.00281. There are 1 homozygotes in gnomad4. There are 112 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 273 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.166G>A	p.Val56Met	missense_variant	3/15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1 linkuse as main transcript	c.-369G>A		5_prime_UTR_variant	4/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 linkuse as main transcript	c.166G>A	p.Val56Met	missense_variant	3/15	1	NM_001943.5	ENSP00000261590	P1

Frequencies

GnomAD3 genomes

AF:

0.00179

AC:

273

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00316

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00189

AC:

471

AN:

249490

Hom.:

AF XY:

0.00187

AC XY:

253

AN XY:

135360

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.000222

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.000417

Gnomad NFE exome

AF:

0.00323

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00251

AC:

3672

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

1767

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00199

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.000562

Gnomad4 NFE exome

AF:

0.00307

Gnomad4 OTH exome

AF:

0.00144

GnomAD4 genome

AF:

0.00179

AC:

273

AN:

152258

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

112

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00316

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00268

Hom.:

Bravo

AF:

0.00182

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000532

AC:

ESP6500EA

AF:

0.00353

AC:

ExAC

AF:

0.00187

AC:

226

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00333

EpiControl

AF:

0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:20Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 27, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DSG2: BP4 -

Arrhythmogenic right ventricular dysplasia 10

Pathogenic:1Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 19, 2018	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2008	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 20, 2017	- -

not specified

Uncertain:1Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 18, 2015	p.Val56Met in exon 3 of DSG2: This variant has been reported in at least 4 indiv iduals with ARVC and was initially believed to be pathogenic (Syrris 2007, Bhuiy an 2009, Den Haan 2009, Christensen 2010, Quarta 2011). However, it has been ide ntified in 0.3% (185/66660) of European chromosomes (including 1 homozygous indi vidual) by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs121913013), strongly arguing against a disease causing role when pres ent in isolation. There is some evidence that the p.Val56Met variant may predisp ose to dilated cardiomyopathy as Posch 2008 detected it in 13/538 DCM probands v ersus 3/617 control individuals (p<0.007), but this study has not been replicate d nor firmly established. In summary, the p.Val56Met variant is unlikely to be d isease causing in isolation, but its increased frequency in patients with DCM ve rsus healthy controls raises the possibility that it acts as a modifier when pre sent together with other variants. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 28, 2023	Variant summary: DSG2 c.166G>A (p.Val56Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 253524 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00025), strongly suggesting that the variant is benign. c.166G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and DCM (Syrris_2007, Posch_2008, Christensen_2010, Dalal_2009, Bhuyian_2009, Quarta_2011). However, the high presence of the variant in the general population and in controls suggests against a disease causing role for this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18382419, 18678517, 17105751, 19039334, 19358943, 20031616, 19955750, 20152563, 20857253, 20716751, 21606390, 20864495, 19569224, 21455723, 20031617, 29038103, 35087879). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=9) and VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 30, 2017	- -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 03, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 08, 2018	- -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Jul 23, 2014

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Jul 23, 2014

- -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 11, 2018

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2018

This alteration is classified as likely 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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2021

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

Dilated cardiomyopathy 1BB

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.17

T;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.83

T;D

M_CAP

Benign

0.055

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

0.0000017

A;A

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.80

N;.

REVEL

Uncertain

0.29

Sift

Uncertain

0.012

D;.

Sift4G

Uncertain

0.052

T;D

Polyphen

1.0

D;.

Vest4

0.51

MVP

0.71

MPC

0.40

ClinPred

0.045

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.12

gMVP

0.74

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