rs144242114

Positions:

• chr18-31080266-T-C
• chr18-31080266-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024422.6(DSC2):​c.1350A>G​(p.Arg450=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,614,090 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (10 hom.)
• Consequence: DSC2 NM_024422.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.00500

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 18-31080266-T-C is Benign according to our data. Variant chr18-31080266-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 36004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31080266-T-C is described in Lovd as [Benign]. Variant chr18-31080266-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.005 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00265 (403/152284) while in subpopulation NFE AF= 0.00409 (278/68014). AF 95% confidence interval is 0.00369. There are 1 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.1350A>G	p.Arg450=	synonymous_variant	10/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1350A>G	p.Arg450=	synonymous_variant	10/17		NP_004940.1
DSC2	NM_001406506.1	c.921A>G	p.Arg307=	synonymous_variant	10/16		NP_001393435.1
DSC2	NM_001406507.1	c.921A>G	p.Arg307=	synonymous_variant	10/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1350A>G	p.Arg450=	synonymous_variant	10/16	1	NM_024422.6	ENSP00000280904	P1
DSC2	ENST00000251081.8	c.1350A>G	p.Arg450=	synonymous_variant	10/17	1		ENSP00000251081
DSC2	ENST00000648081.1	c.921A>G	p.Arg307=	synonymous_variant	11/17			ENSP00000497441
DSC2	ENST00000682357.1	c.921A>G	p.Arg307=	synonymous_variant	10/16			ENSP00000507826

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 403 AN: 152166 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00409

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00313 AC: 786 AN: 251042 Hom.: 1 AF XY: 0.00315 AC XY: 428 AN XY: 135672

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00421

Gnomad OTH exome AF: 0.00556

GnomAD4 exome AF: 0.00336 AC: 4911 AN: 1461806 Hom.: 10 Cov.: 33 AF XY: 0.00329 AC XY: 2395 AN XY: 727202

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.00941

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.00371

Gnomad4 OTH exome AF: 0.00354

GnomAD4 genome AF: 0.00265 AC: 403 AN: 152284 Hom.: 1 Cov.: 33 AF XY: 0.00238 AC XY: 177 AN XY: 74448

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00409

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00299 Hom.: 0

Bravo AF: 0.00277

EpiCase AF: 0.00387

EpiControl AF: 0.00415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 26, 2021	- -
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. -
Likely 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	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified Benign:5

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	GeneDx	Feb 12, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2012	Arg450Arg in Exon 10 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 0.4% (26/7020) of Europ ean American chromosomes from a broad population by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs144242114). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2018	- -

Cardiomyopathy Benign:4

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	DSC2: BP4, BP7 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

DSC2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.4
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs144242114; hg19: chr18-28660232;