rs868333

Positions:

• chr18-31101940-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (1436 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (1254 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.728

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]

DSCAS (HGNC:):

ACMG classification

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	Protein	UniProt
DSC2	NM_024422.6	c.32A>G	p.Asn11Ser	missense_variant	1/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.32A>G	p.Asn11Ser	missense_variant	1/17		NP_004940.1
DSCAS	NR_110785.1	n.136+217T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.32A>G	p.Asn11Ser	missense_variant	1/16	1	NM_024422.6	ENSP00000280904.6

Frequencies

GnomAD3 genomes AF: 0.0753 AC: 11440 AN: 151912 Hom.: 1430 Cov.: 32

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

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.: 32 AF XY: 0.00714 AC XY: 4851 AN XY: 679378

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.: 32 AF XY: 0.0728 AC XY: 5411 AN XY: 74294

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: 66 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

not specified Benign:4

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)	-	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiomyopathy Benign:3

Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -
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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	T
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	N
LIST_S2	Benign	0.095	T;T
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.1	N;N
PrimateAI	Benign	0.44	T
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	T
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

Other links and lift over

dbSNP: rs868333; hg19: chr18-28681903;