rs796960313

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBS1BS2

The NM_024422.6(DSC2):c.2686_2687dupGA(p.Ala897LysfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.0106 in 1,613,982 control chromosomes in the GnomAD database, including 114 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 11 hom., cov: 32)

Exomes 𝑓: 0.011 ( 103 hom. )

Consequence

DSC2
NM_024422.6 frameshift

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:21

Conservation

PhyloP100: 5.14

Publications

18 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: Benign. The variant received -14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00702 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BP6

Variant 18-31068033-T-TTC is Benign according to our data. Variant chr18-31068033-T-TTC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00872 (1327/152258) while in subpopulation NFE AF = 0.0146 (991/68012). AF 95% confidence interval is 0.0138. There are 11 homozygotes in GnomAd4. There are 633 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR,AD,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6 link	c.2686_2687dupGA	p.Ala897LysfsTer4	frameshift_variant	Exon 16 of 16	ENST00000280904.11	NP_077740.1	Q02487-1
DSC2	NM_001406506.1 link	c.2257_2258dupGA	p.Ala754LysfsTer4	frameshift_variant	Exon 16 of 16		NP_001393435.1
DSC2	NM_004949.5 link	c.188_189dupGA		3_prime_UTR_variant	Exon 17 of 17		NP_004940.1	Q02487-2
DSC2	NM_001406507.1 link	c.188_189dupGA		3_prime_UTR_variant	Exon 17 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11 link	c.2686_2687dupGA	p.Ala897LysfsTer4	frameshift_variant	Exon 16 of 16	1	NM_024422.6	ENSP00000280904.6		Q02487-1

Frequencies

GnomAD3 genomes

AF:

0.00872

AC:

1327

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.00623

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00915

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00843

AC:

2119

AN:

251230

AF XY:

0.00854

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00561

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00915

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.00962

GnomAD4 exome

AF:

0.0108

AC:

15742

AN:

1461724

Hom.:

103

Cov.:

AF XY:

0.0106

AC XY:

7673

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33478

American (AMR)

AF:

0.00548

AC:

245

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00161

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.00340

AC:

293

AN:

86254

European-Finnish (FIN)

AF:

0.0103

AC:

552

AN:

53406

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0126

AC:

13968

AN:

1111922

Other (OTH)

AF:

0.00907

AC:

548

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

763

1526

2290

3053

3816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

494

988

1482

1976

2470

<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:

0.00872

AC:

1327

AN:

152258

Hom.:

Cov.:

AF XY:

0.00850

AC XY:

633

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41578

American (AMR)

AF:

0.00622

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00915

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0146

AC:

991

AN:

68012

Other (OTH)

AF:

0.0109

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

140

209

279

349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0117

Hom.:

Bravo

AF:

0.00808

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0126

EpiControl

AF:

0.0130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Jan 14, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala897fs in exon 16 of DSC2: This variant is not expected to have clinical signi ficance because it has been identified in 1.3% (111/8254) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/). This variant leads to a frameshift starting at pos ition 897 and a subsequent truncation that removes the terminal amino acid of th e DSC2 protein. Although it was initially reported in 3 Caucasian individuals wi th ARVC probands while absent from 400 ethnically matched control alleles, it ha s subsequently been detected in several control cohorts at frequencies that argu e against a disease causing role (0.8%-1.5%, see http://arvcdatabase.info). The overall frequency of this variant strongly argues against a primary disease-caus ing role, although we cannot rule out that it may modify disease severity when p resent with other disease-causing variants. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jul 24, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 31, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular dysplasia 11

Uncertain:1Benign:5

Dec 09, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2010

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 31, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DSC2: BS1, BS2 -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:2

May 24, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Jul 01, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary familial hypertrophic cardiomyopathy

Benign:1

Nov 08, 2013

Blueprint Genetics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 15, 2013

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

No disease association in appropriately sized case-control study(ies) -

Familial isolated arrhythmogenic right ventricular dysplasia

Benign:1

Jul 07, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.1

Mutation Taster

=136/64

polymorphism

(source)

Splicing

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