18-31069076-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024422.6(DSC2):c.2326A>G(p.Ile776Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,930 control chromosomes in the GnomAD database, including 12,799 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I776M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 3924 hom., cov: 32)

Exomes 𝑓: 0.096 ( 8875 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 0.0600

Publications

34 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.502965E-4).

BP6

Variant 18-31069076-T-C is Benign according to our data. Variant chr18-31069076-T-C is described in ClinVar as Benign. ClinVar VariationId is 46178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6 link	c.2326A>G	p.Ile776Val	missense_variant	Exon 15 of 16	ENST00000280904.11	NP_077740.1	Q02487-1
DSC2	NM_004949.5 link	c.2326A>G	p.Ile776Val	missense_variant	Exon 15 of 17		NP_004940.1	Q02487-2
DSC2	NM_001406506.1 link	c.1897A>G	p.Ile633Val	missense_variant	Exon 15 of 16		NP_001393435.1
DSC2	NM_001406507.1 link	c.1897A>G	p.Ile633Val	missense_variant	Exon 15 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11 link	c.2326A>G	p.Ile776Val	missense_variant	Exon 15 of 16	1	NM_024422.6	ENSP00000280904.6		Q02487-1

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26841

AN:

151972

Hom.:

3899

Cov.:

show subpopulations

Gnomad AFR

AF:

0.400

Gnomad AMI

AF:

0.127

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.0971

Gnomad EAS

AF:

0.0961

Gnomad SAS

AF:

0.0701

Gnomad FIN

AF:

0.0531

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0857

Gnomad OTH

AF:

0.139

GnomAD2 exomes

AF:

0.116

AC:

29026

AN:

251110

AF XY:

0.105

show subpopulations

Gnomad AFR exome

AF:

0.416

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.100

Gnomad EAS exome

AF:

0.100

Gnomad FIN exome

AF:

0.0578

Gnomad NFE exome

AF:

0.0835

Gnomad OTH exome

AF:

0.0908

GnomAD4 exome

AF:

0.0955

AC:

139653

AN:

1461840

Hom.:

8875

Cov.:

AF XY:

0.0929

AC XY:

67592

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.410

AC:

13725

AN:

33480

American (AMR)

AF:

0.175

AC:

7834

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.102

AC:

2663

AN:

26134

East Asian (EAS)

AF:

0.0928

AC:

3685

AN:

39694

South Asian (SAS)

AF:

0.0660

AC:

5693

AN:

86254

European-Finnish (FIN)

AF:

0.0598

AC:

3197

AN:

53420

Middle Eastern (MID)

AF:

0.0995

AC:

574

AN:

5768

European-Non Finnish (NFE)

AF:

0.0864

AC:

96100

AN:

1111978

Other (OTH)

AF:

0.102

AC:

6182

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

7868

15735

23603

31470

39338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3832

7664

11496

15328

19160

<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:

0.177

AC:

26926

AN:

152090

Hom.:

3924

Cov.:

AF XY:

0.175

AC XY:

13018

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.400

AC:

16580

AN:

41412

American (AMR)

AF:

0.153

AC:

2343

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0971

AC:

337

AN:

3470

East Asian (EAS)

AF:

0.0959

AC:

496

AN:

5170

South Asian (SAS)

AF:

0.0701

AC:

338

AN:

4820

European-Finnish (FIN)

AF:

0.0531

AC:

564

AN:

10612

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0857

AC:

5829

AN:

68014

Other (OTH)

AF:

0.139

AC:

294

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

955

1910

2864

3819

4774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.112

Hom.:

6945

Bravo

AF:

0.196

TwinsUK

AF:

0.0874

AC:

324

ALSPAC

AF:

0.0861

AC:

332

ESP6500AA

AF:

0.401

AC:

1767

ESP6500EA

AF:

0.0837

AC:

720

ExAC

AF:

0.119

AC:

14439

Asia WGS

AF:

0.124

AC:

432

AN:

3478

EpiCase

AF:

0.0814

EpiControl

AF:

0.0739

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 06, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: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

- -

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular dysplasia 11

Benign:5

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 04, 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

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiomyopathy

Benign:2

Oct 10, 2022

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 19, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27153395, 19863551, 25445213) -

Cardiovascular phenotype

Benign:1

Jun 21, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Familial isolated arrhythmogenic right ventricular dysplasia

Benign:1

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.19

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.045

T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.042

T;T;T

MetaRNN

Benign

0.00035

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.8

N;N;.

PhyloP100

0.060

PrimateAI

Benign

0.32

PROVEAN

Benign

0.18

N;N;.

REVEL

Benign

0.10

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.019

MPC

0.063

ClinPred

0.00087

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.024

gMVP

0.17

Mutation Taster

=99/1

polymorphism (auto)

(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