rs151024019

Positions:

• chr18-31070782-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_024422.6(DSC2):​c.2194T>G​(p.Leu732Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,613,992 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (7 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:17
• Conservation: PhyloP100: 0.170

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008374423).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00127 (193/152338) while in subpopulation NFE AF= 0.002 (136/68018). AF 95% confidence interval is 0.00173. There are 0 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2194T>G	p.Leu732Val	missense_variant	14/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2194T>G	p.Leu732Val	missense_variant	14/17		NP_004940.1
DSC2	NM_001406506.1	c.1765T>G	p.Leu589Val	missense_variant	14/16		NP_001393435.1
DSC2	NM_001406507.1	c.1765T>G	p.Leu589Val	missense_variant	14/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2194T>G	p.Leu732Val	missense_variant	14/16	1	NM_024422.6	ENSP00000280904	P1
DSC2	ENST00000251081.8	c.2194T>G	p.Leu732Val	missense_variant	14/17	1		ENSP00000251081
DSC2	ENST00000648081.1	c.1765T>G	p.Leu589Val	missense_variant	15/17			ENSP00000497441
DSC2	ENST00000682357.1	c.1765T>G	p.Leu589Val	missense_variant	14/16			ENSP00000507826

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00114 AC: 287 AN: 251298 Hom.: 1 AF XY: 0.00115 AC XY: 156 AN XY: 135816

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00197 AC: 2884 AN: 1461654 Hom.: 7 Cov.: 31 AF XY: 0.00188 AC XY: 1370 AN XY: 727128

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00247

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74492

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00200

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00208 Hom.: 0

Bravo AF: 0.00127

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2021	This variant is associated with the following publications: (PMID: 21606390, 21606396, 23299917, 20031616, 21859740, 24055113, 23861362, 23396983, 24967631, 25447171, 21636032, 26899768, 26332594) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	DSC2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 06, 2016	p.Leu732Val in exon 14 of DSC2: This variant been reported in 4 individuals with ARVC and 1 individual DCM and absent from 700 control chromosomes (Bhuiyan 2009 , Cox 2011, Garcia-Pavia 2011, Quarta 2011). However, it has been identified in 0.2% (134/66698) of European chromosomes by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs151024019). In addition, Leucine (Le u) at position 732 is not conserved in evolution and the variant is present in f our mammals, suggesting that a change to this position may be tolerated. In summ ary, this variant is likely benign but a modifying role cannot be excluded. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given presence in controls and somewhat weak case data (reviewed below) we consider this variant to be of uncertain significance. This variant has been reported in association with ARVC in the literature, although the clinical significance of this variant is unclear. It has been reported in 4 individuals with ARVC and 1 individual with DCM (Bhuiyan 2009; Cox 2011; Garcia-Pavia 2011; Quarta 2011). In these studies it was absent from 350 total control individuals. However, it has also been identified in 0.13% of European American chromosomes in the NHLBI ESP dataset. Bhuiyan et al. 2009 reported this variant in one individual with ARVC who also harbored another missense variant in the DSG2 gene, and both individuals were absent from 150 ethnically matched control individuals. Cox et al. 2011 reported this variant as an unclassified variant after observing it in two patients with ARVC who also harbored additional pathogenic variants or novel variants. This variant commonly occurs together with the DSG2 Val392Ile variant, which is also likely benign, suggesting that these variants are present on the same allele. This is a conservative amino acid change where a nonpolar leucine residue is exchanged for a nonpolar valine residue. The leucine at codon 732 is not well conserved across mammalian species. In silico analysis consistently predicts this variant to be benign (PolyPhen predicts this variant to be probably benign mutation taster predicts this variant to be a polymorphism). In total this variant has been seen in 14 out of ~6850 control individuals from the literature and publicly available population datasets. It is present in 14 total individuals of approximately 6500 individuals of European American and African American ancestry in the NHLBI Exome Sequencing Project dataset, for an allele frequency of .11%. This variant is present in dbSNP as rs151024019, submitted by ESP and 1000Genomes. It is also present at low frequency in 1000Genomes (allele frequency of .05%). Finally, this variant is present in the ExAC database in 146/ 61,434 individuals of varying ancestries (as of December 7, 2014). Presence of a variant among individuals in the general population cannot definitively rule it out as the cause of disease, as even gold-standard pathogenic cardiomyopathy variants have been found in population datasets (Pan et al. 2012). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 08, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 23, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Arrhythmogenic right ventricular cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 18, 2015	- -

Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

DSC2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2021

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

Primary familial hypertrophic cardiomyopathy Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 17, 2014

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 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	0.073
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	10
DANN	Benign	0.68
DEOGEN2	Benign	0.065	T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0084	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L;L;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.71	N;N;.
REVEL	Benign	0.26
Sift	Benign	0.90	T;T;.
Sift4G	Benign	0.78	T;T;.
Polyphen		0.0020	B;B;.
Vest4		0.69
MVP		0.33
MPC		0.084
ClinPred		0.0072	T
GERP RS		-4.8
Varity_R		0.032
gMVP		0.47

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: rs151024019; hg19: chr18-28650748;