18-31071829-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_024422.6(DSC2):c.1901G>A(p.Arg634His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,612,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R634L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.0560

Publications

6 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0107584).

BP6

Variant 18-31071829-C-T is Benign according to our data. Variant chr18-31071829-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46172.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6 link	c.1901G>A	p.Arg634His	missense_variant	Exon 13 of 16	ENST00000280904.11	NP_077740.1	Q02487-1
DSC2	NM_004949.5 link	c.1901G>A	p.Arg634His	missense_variant	Exon 13 of 17		NP_004940.1	Q02487-2
DSC2	NM_001406506.1 link	c.1472G>A	p.Arg491His	missense_variant	Exon 13 of 16		NP_001393435.1
DSC2	NM_001406507.1 link	c.1472G>A	p.Arg491His	missense_variant	Exon 13 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11 link	c.1901G>A	p.Arg634His	missense_variant	Exon 13 of 16	1	NM_024422.6	ENSP00000280904.6		Q02487-1

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00585

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000567

AC:

142

AN:

250254

AF XY:

0.000584

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00576

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000303

AC:

443

AN:

1460626

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

199

AN XY:

726722

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.0000224

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00693

AC:

369

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000495

AC:

AN:

1111074

Other (OTH)

AF:

0.000265

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

112

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:

0.000473

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41572

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00585

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68020

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000798

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000428

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Nov 30, 2015

Blueprint Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Arg634His varia nt (DSC2) has been identified in 1 individual with ARVC tested by our laboratory , who also carried a second variant sufficient to cause disease. This variant ha s also been identified in 3/7020 European American chromosomes by the NHLBI Exom e Sequencing Project in a broad population (http://evs.gs.washington.edu/EVS). C omputational analyses (biochemical amino acid properties, conservation, AlignGVG D, PolyPhen2, and SIFT) suggest that the Arg634His variant may not impact the pr otein and opossum carries a Histadine (His, this variant) at this position, thou gh this information is not predictive enough to rule out pathogenicity. Collecti vely this data suggests that this variant may be benign, but additional informat ion is needed to fully assess its clinical significance. -

Oct 31, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DSC2 c.1901G>A (p.Arg634His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 281656 control chromosomes, predominantly at a frequency of 0.0059 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 36 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1901G>A has been reported in the literature in individuals affected with long QT syndrome type 2 (LQT2) and ARVD, suspected DCM or coronary artery disease related sudden cardiac death (Tisma-Dupanovic_2013, Qadri_2017, Vhtalo_2022). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28818065, 23347029, 35087879). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Arrhythmogenic right ventricular dysplasia 11

Benign:2

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 28, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Jan 10, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Oct 05, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 20, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.090

T;.;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.092

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.040

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.5

M;M;.

PhyloP100

0.056

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.3

N;N;.

REVEL

Benign

0.077

Sift

Benign

0.53

T;T;.

Sift4G

Benign

0.55

T;T;.

Polyphen

0.11

B;B;.

Vest4

0.23

MVP

0.54

MPC

0.10

ClinPred

0.036

GERP RS

4.3

Varity_R

0.088

gMVP

0.52

Mutation Taster

=88/12

polymorphism

(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