NM_024422.6:c.394C>T

Variant names:

Variant summary

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

The NM_024422.6(DSC2):c.394C>T(p.Arg132Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,613,808 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 3.77

Publications

17 publications found

Variant links:

Genes affected

DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

DSC2 Gene-Disease associations (from GenCC):

familial isolated arrhythmogenic right ventricular dysplasia
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
arrhythmogenic right ventricular dysplasia 11
Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
colorectal adenoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DSC2 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, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6 link	c.394C>T	p.Arg132Cys	missense_variant	Exon 4 of 16	ENST00000280904.11	NP_077740.1	Q02487-1
DSC2	NM_004949.5 link	c.394C>T	p.Arg132Cys	missense_variant	Exon 4 of 17		NP_004940.1	Q02487-2
DSC2	NM_001406506.1 link	c.-36C>T		5_prime_UTR_variant	Exon 4 of 16		NP_001393435.1
DSC2	NM_001406507.1 link	c.-36C>T		5_prime_UTR_variant	Exon 4 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11 link	c.394C>T	p.Arg132Cys	missense_variant	Exon 4 of 16	1	NM_024422.6	ENSP00000280904.6		Q02487-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251182

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.000101

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1111908

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

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:

0.0000197

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41396

American (AMR)

AF:

0.0000655

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

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:

0.0000821

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sudden unexplained death

Uncertain:1

Jul 26, 2018

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

DSC2 Arg132Cys has been reported previously in 2 ARVC patients, however both patients also had other DSC2 variants (Fressart V et al., 2010; Ohno S, et al., 2013). We have identified this variant in a proband of south-east asian descent whom presented with cardiac arrest. The patient was also found to have a second variant (PKP2 p.Leu744Serfs*3). Clinical screening did not uncover any abnormal findings, but it is possible that the patient may have a 'concealed' ARVC phenotype. The proband has no family history of any inherited cardiac disease or sudden death. The variant is present at an elevated frequency in the Genome Aggregation Database (MAF= 0.000036, http://gnomad.broadinstitute.org/). In silico tools SIFT, MutationTaster, CADD and PolyPhen-2 all predict the variant to be deleterious. In summary, the variant has been reported in at least 3 probands with multiple variants, it is present in population databases but is still considered rare and in silico tools predict it to be deleterious, therefore based on this conflicting information we classify DSC2 Arg132Cys as a variant of 'uncertain significance'. -

not specified

Uncertain:1

Oct 24, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg132Cys variant in DSC2 has been identified in 3 individuals with ARVC, one of whom carried a likely pathogenic variant in PKP2 and another of whom also carried a frameshift variant in DSC2 (Fressart 2010, Ohno 2013, Wada 2017, LMM data). This variant has been identified in 10/282564 chromosomes by the gnomAD ( http://gnomad.broadinstitute.org). Computational prediction tools and conservati on analysis suggest that the p.Arg132Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary , the clinical significance of the p.Arg132Cys variant is uncertain. ACMG/AMP Cr iteria applied: PP3. -

Arrhythmogenic right ventricular dysplasia 11

Uncertain:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 132 of the DSC2 protein (p.Arg132Cys). This variant is present in population databases (rs727504578, gnomAD 0.02%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 23514727, 33784018). ClinVar contains an entry for this variant (Variation ID: 178972). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DSC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DSC2 function (PMID: 33784018). 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. -

Cardiomyopathy

Uncertain:1

Dec 16, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with cysteine at codon 132 of the DSC2 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). A functional study has shown that, unlike wildtype, this variant can't rescue the cardiovascular phenotypes in DSC2 knockdown zebrafish model (PMID: 33784018). This variant has been reported in an individual affected with cardiac arrest (ClinVar SCV001245073.1) and in four unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 20400443, 23514727, 29178656, 33784018, ClinVar SCV000205460.4). Two of these probands also carried a truncating variant in DSC2 or PKP2 genes (PMID: 20400443, ClinVar SCV001245073.1). Studies with heart samples and cardiomyocytes derived from one of the probands revealed altered electric activity and a marked reduction of DSC2 in both mRNA and protein levels (PMID: 33784018, 35297182). This variant has been identified in 10/282564 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. -

Primary dilated cardiomyopathy

Uncertain:1

Jun 01, 2023

Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

May 01, 2019

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R132C variant (also known as c.394C>T), located in coding exon 4 of the DSC2 gene, results from a C to T substitution at nucleotide position 394. The arginine at codon 132 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), who also had additional cardiac-related variants detected (Fressart V et al. Europace, 2010 Jun;12:861-8; Ohno S et al. Circ. J., 2013 Mar;77:1534-42). This alteration has also been seen in an exome cohort, but detailed cardiovascular history was not provided (Haggerty CM et al. Genet. Med., 2017 11;19:1245-1252). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial isolated arrhythmogenic right ventricular dysplasia

Uncertain:1

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;.

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

-0.058

MutationAssessor

Pathogenic

3.7

H;H

PhyloP100

3.8

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.91

MutPred

0.93

Loss of disorder (P = 0.0268);Loss of disorder (P = 0.0268);

MVP

0.73

MPC

0.50

ClinPred

0.84

GERP RS

3.9

Varity_R

0.27

gMVP

0.88

Mutation Taster

=13/87

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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