rs868333

chr18-31101940-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024422.6(DSC2):c.32A>G(p.Asn11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,529,004 control chromosomes in the GnomAD database, including 2,690 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N11N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.076 ( 1436 hom., cov: 32)

Exomes 𝑓: 0.0081 ( 1254 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.728

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:

DSCAS (HGNC:51116): (DSC1/DSC2 antisense RNA)

DSCAS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009185106).

BP6

Variant 18-31101940-T-C is Benign according to our data. Variant chr18-31101940-T-C is described in ClinVar as [Benign]. Clinvar id is 46191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31101940-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSC2	NM_024422.6 linkuse as main transcript	c.32A>G	p.Asn11Ser	missense_variant	1/16	ENST00000280904.11
DSCAS	NR_110785.1 linkuse as main transcript	n.136+217T>C		intron_variant, non_coding_transcript_variant
DSC2	NM_004949.5 linkuse as main transcript	c.32A>G	p.Asn11Ser	missense_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.32A>G	p.Asn11Ser	missense_variant	1/16	1	NM_024422.6	P1	Q02487-1
DSCAS	ENST00000581836.2 linkuse as main transcript	n.152+217T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0753

AC:

11440

AN:

151912

Hom.:

1430

Cov.:

show subpopulations

Gnomad AFR

AF:

0.262

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0244

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000980

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.0449

GnomAD3 exomes

AF:

0.0137

AC:

1685

AN:

122752

Hom.:

170

AF XY:

0.0115

AC XY:

779

AN XY:

67610

show subpopulations

Gnomad AFR exome

AF:

0.263

Gnomad AMR exome

AF:

0.0113

Gnomad ASJ exome

AF:

0.0151

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000848

Gnomad OTH exome

AF:

0.00847

GnomAD4 exome

AF:

0.00811

AC:

11167

AN:

1376984

Hom.:

1254

Cov.:

AF XY:

0.00714

AC XY:

4851

AN XY:

679378

show subpopulations

Gnomad4 AFR exome

AF:

0.278

Gnomad4 AMR exome

AF:

0.0134

Gnomad4 ASJ exome

AF:

0.0153

Gnomad4 EAS exome

AF:

0.000172

Gnomad4 SAS exome

AF:

0.00117

Gnomad4 FIN exome

AF:

0.000226

Gnomad4 NFE exome

AF:

0.000587

Gnomad4 OTH exome

AF:

0.0190

GnomAD4 genome

AF:

0.0755

AC:

11478

AN:

152020

Hom.:

1436

Cov.:

AF XY:

0.0728

AC XY:

5411

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.262

Gnomad4 AMR

AF:

0.0243

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.000983

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00119

Gnomad4 OTH

AF:

0.0445

Alfa

AF:

0.0333

Hom.:

140

Bravo

AF:

0.0878

ExAC

AF:

0.0113

AC:

225

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11

Benign:5

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 14, 2008	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Cardiomyopathy

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 29, 2015	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2015

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

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

Cadd

Benign

6.2

Dann

Benign

0.79

DEOGEN2

Benign

0.041

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0034

LIST_S2

Benign

0.095

T;T

MetaRNN

Benign

0.0092

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.1

N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.44

PROVEAN

Benign

0.60

N;N

REVEL

Benign

0.15

Sift

Benign

0.95

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.020

MPC

0.060

ClinPred

0.00092

GERP RS

3.6

Varity_R

0.024

gMVP

0.29

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

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