rs145560678

Positions:

• chr18-31086611-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024422.6(DSC2):​c.907G>A​(p.Val303Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,614,094 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (8 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.758

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011647344).
• BP6: Variant 18-31086611-C-T is Benign according to our data. Variant chr18-31086611-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46202.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=4, Uncertain_significance=1}. Variant chr18-31086611-C-T is described in Lovd as [Benign]. Variant chr18-31086611-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000486 (74/152234) while in subpopulation SAS AF= 0.00787 (38/4828). AF 95% confidence interval is 0.00589. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.907G>A	p.Val303Met	missense_variant	7/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.907G>A	p.Val303Met	missense_variant	7/17		NP_004940.1
DSC2	NM_001406506.1	c.478G>A	p.Val160Met	missense_variant	7/16		NP_001393435.1
DSC2	NM_001406507.1	c.478G>A	p.Val160Met	missense_variant	7/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.907G>A	p.Val303Met	missense_variant	7/16	1	NM_024422.6	ENSP00000280904	P1
DSC2	ENST00000251081.8	c.907G>A	p.Val303Met	missense_variant	7/17	1		ENSP00000251081
DSC2	ENST00000648081.1	c.478G>A	p.Val160Met	missense_variant	8/17			ENSP00000497441
DSC2	ENST00000682357.1	c.478G>A	p.Val160Met	missense_variant	7/16			ENSP00000507826

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00108 AC: 271 AN: 251432 Hom.: 1 AF XY: 0.00139 AC XY: 189 AN XY: 135886

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00679

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000646 AC: 944 AN: 1461860 Hom.: 8 Cov.: 31 AF XY: 0.000846 AC XY: 615 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00653

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000253

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74416

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000474 Hom.: 1

Bravo AF: 0.000283

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00119 AC: 145

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 31, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 08, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 02, 2020	Variant summary: DSC2 c.907G>A (p.Val303Met) results in a conservative amino acid change located in the Cadherin-like domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 252686 control chromosomes, predominantly at a frequency of 0.0068 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 680-fold the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.907G>A has been reported in the literature in at least one individual affected with cardiomyopathy (e.g. Garcia-Pavia_2011), but also in healthy controls (e.g. Kapplinger_2011). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant as benign/likely benign (n=8) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 15, 2016	p.Val303Met in exon 7 of DSC2: This variant has been identified in 0.7% (120/165 12) of South Asian chromosomes, including 1 homozygote, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145560678). This vari ant was previously reported in 1 individual with DCM (Garcia-Pavia 2011). Howeve r, given the high frequency of this variant in the general population, it is not expected to have clinical significance. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	DSC2: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 20, 2018	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2018

This alteration is classified as likely 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	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.089
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.89	D;D;D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	0.86	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	D;D;.
REVEL	Benign	0.20
Sift	Uncertain	0.014	D;D;.
Sift4G	Uncertain	0.035	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.33
MVP		0.58
MPC		0.27
ClinPred		0.067	T
GERP RS		3.8
Varity_R		0.25
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145560678; hg19: chr18-28666574; COSMIC: COSV51862738;