chr18-31068033-T-TTC

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 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	UniProt
DSC2	ENST00000280904.11 link	c.2686_2687dupGA	p.Ala897LysfsTer4	frameshift_variant	Exon 16 of 16	1	NM_024422.6	ENSP00000280904.6	Q02487-1
DSC2	ENST00000251081 link	c.188_189dupGA		3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000251081.6	Q02487-2
DSC2	ENST00000648081.1 link	c.2257_2258dupGA	p.Ala754LysfsTer4	frameshift_variant	Exon 17 of 17			ENSP00000497441.1	A0A3B3ISU0
DSC2	ENST00000682357.1 link	c.2257_2258dupGA	p.Ala754LysfsTer4	frameshift_variant	Exon 16 of 16			ENSP00000507826.1	A0A3B3ISU0

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

GnomAD3 exomes

AF:

0.00843

AC:

2119

AN:

251230

Hom.:

AF XY:

0.00854

AC XY:

1159

AN XY:

135792

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 SAS exome

AF:

0.00297

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

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.00548

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00340

Gnomad4 FIN exome

AF:

0.0103

Gnomad4 NFE exome

AF:

0.0126

Gnomad4 OTH exome

AF:

0.00907

GnomAD4 genome

AF:

0.00872

AC:

1327

AN:

152258

Hom.:

Cov.:

AF XY:

0.00850

AC XY:

633

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.00622

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00915

Gnomad4 NFE

AF:

0.0146

Gnomad4 OTH

AF:

0.0109

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

Arrhythmogenic right ventricular dysplasia 11

Uncertain:1Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 09, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2010

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Benign:6

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

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 31, 2013

Eurofins Ntd Llc (ga)

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

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DSC2: BS1, BS2 -

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:2

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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

Splicing

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