rs117812913

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_024422.6(DSC2):c.351A>G(p.Thr117=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00935 in 1,611,618 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 90 hom. )

Consequence

DSC2
NM_024422.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.631

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 18-31092104-T-C is Benign according to our data. Variant chr18-31092104-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 46188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31092104-T-C is described in Lovd as [Benign]. Variant chr18-31092104-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.631 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00798 (1215/152332) while in subpopulation NFE AF= 0.0132 (897/68030). AF 95% confidence interval is 0.0125. There are 8 homozygotes in gnomad4. There are 600 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSC2	NM_024422.6 linkuse as main transcript	c.351A>G	p.Thr117=	synonymous_variant	3/16	ENST00000280904.11
DSC2	NM_004949.5 linkuse as main transcript	c.351A>G	p.Thr117=	synonymous_variant	3/17
DSC2	NM_001406506.1 linkuse as main transcript	c.-79A>G		5_prime_UTR_variant	3/16
DSC2	NM_001406507.1 linkuse as main transcript	c.-79A>G		5_prime_UTR_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.351A>G	p.Thr117=	synonymous_variant	3/16	1	NM_024422.6	P1	Q02487-1
DSC2	ENST00000251081.8 linkuse as main transcript	c.351A>G	p.Thr117=	synonymous_variant	3/17	1			Q02487-2
DSC2	ENST00000648081.1 linkuse as main transcript	c.-116A>G		5_prime_UTR_variant	3/17
DSC2	ENST00000682357.1 linkuse as main transcript	c.-79A>G		5_prime_UTR_variant	3/16

Frequencies

GnomAD3 genomes

AF:

0.00798

AC:

1215

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0175

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0132

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00837

AC:

2098

AN:

250692

Hom.:

AF XY:

0.00820

AC XY:

1111

AN XY:

135552

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00290

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00255

Gnomad FIN exome

AF:

0.0186

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.00884

GnomAD4 exome

AF:

0.00949

AC:

13847

AN:

1459286

Hom.:

Cov.:

AF XY:

0.00919

AC XY:

6674

AN XY:

725994

show subpopulations

Gnomad4 AFR exome

AF:

0.00129

Gnomad4 AMR exome

AF:

0.00284

Gnomad4 ASJ exome

AF:

0.00138

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00246

Gnomad4 FIN exome

AF:

0.0197

Gnomad4 NFE exome

AF:

0.0107

Gnomad4 OTH exome

AF:

0.00833

GnomAD4 genome

AF:

0.00798

AC:

1215

AN:

152332

Hom.:

Cov.:

AF XY:

0.00805

AC XY:

600

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0175

Gnomad4 NFE

AF:

0.0132

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.0102

Hom.:

Bravo

AF:

0.00614

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00954

EpiControl

AF:

0.00972

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11

Benign:5

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 23, 2012	Thr117Thr in Exon 03 of DSC2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 1.2% (81/7016) of Europ ean American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs117812913). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Aug 07, 2019	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DSC2: BP4, BP7, BS1, BS2 -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 18, 2016	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

Cadd

Benign

7.6

Dann

Benign

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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