rs121913012

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001943.5(DSG2):c.991G>A(p.Glu331Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:7

Conservation

PhyloP100: 9.02

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
arrhythmogenic right ventricular dysplasia 10
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy 1BB
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

DSG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5 link	c.991G>A	p.Glu331Lys	missense_variant	Exon 8 of 15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1 link	c.457G>A	p.Glu153Lys	missense_variant	Exon 9 of 16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 link	c.991G>A	p.Glu331Lys	missense_variant	Exon 8 of 15	1	NM_001943.5	ENSP00000261590.8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

249402

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111990

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000139

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10

Pathogenic:1Uncertain:2

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 331 of the DSG2 protein (p.Glu331Lys). This variant is present in population databases (rs121913012, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 24070718, 28471438, 30830208). ClinVar contains an entry for this variant (Variation ID: 16816). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 10 (ARVD; MIM#610193). (I) 0107 - This gene is associated with autosomal dominant disease. It is commonly associated with dominant inheritance for arrhythmogenic right ventricular dysplasia 10 (MIM#610193). (I) 0112 - The ARVD condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (4 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cadherin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported five times in ClinVar as a VUS and reported in the literature as a VUS in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 16505173, 29750433, 28471438). (I) 0906 - Segregation evidence for this variant is inconclusive. This variant was identified in two affected siblings both also compound heterozygous for a splice site variant. The two children of one of these siblings both carry the missense variant and no splice site variant, these two individuals are either unaffected or of unknown disease status (PMID: 16505173). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Mar 07, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Cardiomyopathy

Uncertain:2

Sep 08, 2017

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 10, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glutamic acid with lysine at codon 331 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 16505173, 21606390, 29750433) and in three unaffected relatives from one of the families (PMID: 16505173, 24070718, 26138720). One of the probands was compound heterozygous with a splice variant (PMID 26138720). This variant has been identified in 4/249402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:2

Oct 02, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The c.991G>A (p.Glu331Lys) missense variant changes evolutionary conserved Glu to Lys, which changes the charge from negative to positive. 3/4 in silico tools predict this variant to be damaging. This variant lies in cadherin 3 domain (source ARVC db) and other missense changes have also been detected in and around this codon such as p.D326V, p.N330D, p.I333T and p.T335A (source: HGMD) in ARVC patients. This suggests that this variant may alter protein functionality. The variant is found in only 3 alleles across 120630 chromosomes in ExAC. Although the allele frequency in general population is lower than the maximal expected allele frequency based on the disease prevalence of ARVC, the possibility of this variant being a rare polymorphism cannot be ruled out. Two studies reported this variant in two ARVD families; however, segregation analysis in one family does not prove the variant as a high penetrance disease-causing variant.

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

May 14, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in two siblings with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, both individuals also harbor a splice site variant in the DSG2 gene (Pilichou et al., 2006); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 16816; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31402444, 16505173)

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

M_CAP

Benign

0.074

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-0.56

MutationAssessor

Pathogenic

3.4

PhyloP100

9.0

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.59

Sift

Uncertain

0.0040

Sift4G

Benign

0.10

Vest4

0.93

ClinPred

0.91

GERP RS

5.4

Varity_R

0.87

gMVP

0.88

Mutation Taster

=11/89

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over