rs148185335

chr18-31074784-G-Achr18-31074784-G-Cchr18-31074784-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_024422.6(DSC2):c.1787C>T(p.Ala596Val) variant causes a missense change. The variant allele was found at a frequency of 0.000827 in 1,613,922 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A596T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (6 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16
• Conservation: PhyloP100: 5.44

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011357248).
• BP6: Variant 18-31074784-G-A is Benign according to our data. Variant chr18-31074784-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46171.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, Benign=1, Uncertain_significance=1}. Variant chr18-31074784-G-A is described in Lovd as [Benign]. Variant chr18-31074784-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000743 (113/152162) while in subpopulation SAS AF= 0.00332 (16/4822). AF 95% confidence interval is 0.00208. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.1787C>T	p.Ala596Val	missense_variant	12/16	ENST00000280904.11
DSC2	NM_004949.5	c.1787C>T	p.Ala596Val	missense_variant	12/17
DSC2	NM_001406506.1	c.1358C>T	p.Ala453Val	missense_variant	12/16
DSC2	NM_001406507.1	c.1358C>T	p.Ala453Val	missense_variant	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.1787C>T	p.Ala596Val	missense_variant	12/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.1787C>T	p.Ala596Val	missense_variant	12/17	1
DSC2	ENST00000648081.1	c.1358C>T	p.Ala453Val	missense_variant	13/17
DSC2	ENST00000682357.1	c.1358C>T	p.Ala453Val	missense_variant	12/16

Frequencies

GnomAD3 genomes AF: 0.000750 AC: 114 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00119 AC: 298 AN: 251052 Hom.: 1 AF XY: 0.00139 AC XY: 189 AN XY: 135680

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00327

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000835 AC: 1221 AN: 1461760 Hom.: 6 Cov.: 32 AF XY: 0.000974 AC XY: 708 AN XY: 727166

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00282

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.000717

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000743 AC: 113 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000780 AC XY: 58 AN XY: 74372

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.000867

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000737

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00124 AC: 151

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DSC2: BS2 -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 29, 2017	Variant summary: The DSC2 c.1787C>T (p.Ala596Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 152/121170 control chromosomes, predominantly observed in the subpopulation at an allele frequency of 0.0029755 (49/16468). This frequency is about 298 times the estimated maximal expected allele frequency of a pathogenic DSC2 variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of origin. This variant has been reported in patients with ARVC, HCM, DCM and SIDS (Tan_2010, Lopes_2013, Santori_2015, Haas_2015, and Bottillo_2016). No cosegregation analysis was performed in these studies. In one patient with HCM, another pathogenic variant MYH7 p.V606M was also detected, indicating benign outcome (Lopes_2013). In ClinVar while two clinical diagnostic laboratories have classified this variant as likely benign, three have classified it as VUS. Taken together, this variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2020	This variant is associated with the following publications: (PMID: 26656175, 25163546, 23396983, 23861362, 20031617, 20857253, 25351510, 28600387, 33232181) -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Dec 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 07, 2017	p.Ala596Val in exon 12 of DSC2: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (49/16468) of South Asian chro mosomes, including 1 homozygous individual, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP dbSNP rs148185335). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Arrhythmogenic right ventricular dysplasia 11 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 09, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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	Sep 09, 2019	- -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Aug 10, 2015

- -

DSC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2022

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). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2019

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	Pathogenic	0.68
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.5	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D;D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0070	D;D;.
Sift4G	Uncertain	0.024	D;D;.
Polyphen		0.55	P;P;.
Vest4		0.59
MVP		0.84
MPC		0.085
ClinPred		0.092	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.88

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: rs148185335; hg19: chr18-28654750; COSMIC: COSV51869560;