rs193922639

Positions:

Variant summary

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

The NM_001943.5(DSG2):c.1174G>A(p.Val392Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,614,094 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 13 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:17

Conservation

PhyloP100: 1.68

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07768899).

BP6

Variant 18-31531146-G-A is Benign according to our data. Variant chr18-31531146-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36009.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=7, Uncertain_significance=1}. Variant chr18-31531146-G-A is described in Lovd as [Benign]. Variant chr18-31531146-G-A is described in Lovd as [Likely_benign]. Variant chr18-31531146-G-A is described in Lovd as [Pathogenic]. Variant chr18-31531146-G-A is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00164 (249/152256) while in subpopulation SAS AF= 0.00436 (21/4822). AF 95% confidence interval is 0.00292. There are 1 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 249 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.1174G>A	p.Val392Ile	missense_variant	9/15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1 linkuse as main transcript	c.640G>A	p.Val214Ile	missense_variant	10/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 linkuse as main transcript	c.1174G>A	p.Val392Ile	missense_variant	9/15	1	NM_001943.5	ENSP00000261590	P1
DSG2	ENST00000683614.2 linkuse as main transcript	n.1005G>A		non_coding_transcript_exon_variant	7/7

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

249

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00254

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00219

AC:

545

AN:

249420

Hom.:

AF XY:

0.00243

AC XY:

329

AN XY:

135312

show subpopulations

Gnomad AFR exome

AF:

0.000839

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00608

Gnomad FIN exome

AF:

0.000835

Gnomad NFE exome

AF:

0.00259

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00273

AC:

3984

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

2077

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00625

Gnomad4 FIN exome

AF:

0.00129

Gnomad4 NFE exome

AF:

0.00288

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00164

AC:

249

AN:

152256

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00436

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00254

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00249

Hom.:

Bravo

AF:

0.00142

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000533

AC:

ESP6500EA

AF:

0.00207

AC:

ExAC

AF:

0.00257

AC:

310

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:17

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2020	This variant is associated with the following publications: (PMID: 23812740, 26899768, 25637381, 23299917, 21636032, 24070718, 17105751, 20031616, 20129281, 20829228, 21606390, 21859740, 21606396, 21723241, 23071725, 23396983, 24436435, 24055113, 26138720, 26681313, 27153395, 25985138, 28255936, 29062102, 30885746) -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DSG2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 03, 2015	p.Val392Ile in exon 9 of DSG2: This variant has been reported in many individual s with diverse presentations (ARVC, LQTS1, LDAC, DCM: Syrris 2007, Bhuiyan 2009, Bauce 2010, Klauke 2010, Quarta 2011, Cox 2011, Bauce 2011, Garcia-Parva 2011, LMM unpublished data). However, this variant has also been identified in 0.7% (1 11/16510) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org;dbSNP rs193922639). In addition, valine (Val) at position 392 is poorly conserved in evolution and the variant is present in two species (including 1 mammal), suggesting that a change to this position may be t olerated. In summary, this variant is likely benign but a modifying role cannot be excluded. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2019	Variant summary: DSG2 c.1174G>A (p.Val392Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 249420 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 200 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. Though c.1174G>A has been reported in the literature in individuals affected with ARVC/D, LQTS and DCM, including families showing incomplete co-segregation with disease, in addition, multiple co-occurrences with other pathogenic variants have been noted (PKP2 c.148_151delACAG (p.Thr50fsX61), Bauce_2010, Rigato_2013; PKP2 c.235C>T (p.Arg79X), Cox _2011), providing supporting evidence for a benign role. Publication also reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect of this variant (Gaertner_2012, Dieding_2017). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as Benign (2x), Likely benign (3x) or VUS (1x). Based on the evidence outlined above, the variant was classified as benign. -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 11, 2018	- -

Arrhythmogenic right ventricular dysplasia 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Arrhythmogenic right ventricular dysplasia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 25, 2019

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.11

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.48

M_CAP

Benign

0.029

MetaRNN

Benign

0.078

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

MutationTaster

Benign

2.5e-11

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.51

REVEL

Benign

0.27

Sift

Uncertain

0.017

Sift4G

Uncertain

0.032

Polyphen

0.0080

Vest4

0.082

MVP

0.35

MPC

0.059

ClinPred

0.0093

GERP RS

0.98

Varity_R

0.071

gMVP

0.28

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