rs143413607

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024422.6(DSC2):c.2471C>T(p.Ser824Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000508 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S824A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 6.53

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSC2	NM_024422.6 linkuse as main transcript	c.2471C>T	p.Ser824Leu	missense_variant	15/16	ENST00000280904.11
DSC2	NM_004949.5 linkuse as main transcript	c.2471C>T	p.Ser824Leu	missense_variant	15/17
DSC2	NM_001406506.1 linkuse as main transcript	c.2042C>T	p.Ser681Leu	missense_variant	15/16
DSC2	NM_001406507.1 linkuse as main transcript	c.2042C>T	p.Ser681Leu	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.2471C>T	p.Ser824Leu	missense_variant	15/16	1	NM_024422.6	P1	Q02487-1
DSC2	ENST00000251081.8 linkuse as main transcript	c.2471C>T	p.Ser824Leu	missense_variant	15/17	1			Q02487-2
DSC2	ENST00000648081.1 linkuse as main transcript	c.2042C>T	p.Ser681Leu	missense_variant	16/17
DSC2	ENST00000682357.1 linkuse as main transcript	c.2042C>T	p.Ser681Leu	missense_variant	15/16

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000916

AC:

AN:

251032

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000164

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000554

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000502

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:2

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 30, 2015	- -

Arrhythmogenic right ventricular dysplasia 11

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 01, 2023

This missense variant replaces serine with leucine at codon 824 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495, 24832006). This variant was also detected in a post-mortem heart tissue sample from an individual with clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (PMID: 24832006). This variant has also been identified in 29/282414 chromosomes (18/24954 African chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Familial isolated arrhythmogenic right ventricular dysplasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

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

0.16

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.096

MetaRNN

Uncertain

0.49

T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

3.0

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.4

D;D;.

REVEL

Uncertain

0.63

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.0040

D;D;.

Polyphen

0.95

P;D;.

Vest4

0.87

MVP

0.93

MPC

0.37

ClinPred

0.25

GERP RS

5.5

Varity_R

0.20

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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