rs201015785

chr18-31086716-T-Cchr18-31086716-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP6 BS1

The NM_024422.6(DSC2):c.802A>G(p.Thr268Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T268P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• Conservation: PhyloP100: 2.65

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 18-31086716-T-C is Benign according to our data. Variant chr18-31086716-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178019.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=4}. Variant chr18-31086716-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000103 (150/1461808) while in subpopulation MID AF= 0.00191 (11/5762). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4_exome. There are 75 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.802A>G	p.Thr268Ala	missense_variant	7/16	ENST00000280904.11
DSC2	NM_004949.5	c.802A>G	p.Thr268Ala	missense_variant	7/17
DSC2	NM_001406506.1	c.373A>G	p.Thr125Ala	missense_variant	7/16
DSC2	NM_001406507.1	c.373A>G	p.Thr125Ala	missense_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.802A>G	p.Thr268Ala	missense_variant	7/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.802A>G	p.Thr268Ala	missense_variant	7/17	1
DSC2	ENST00000648081.1	c.373A>G	p.Thr125Ala	missense_variant	8/17
DSC2	ENST00000682357.1	c.373A>G	p.Thr125Ala	missense_variant	7/16

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 251258 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135800

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000103 AC: 150 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.000103 AC XY: 75 AN XY: 727198

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000800

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74472

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000696 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 24, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 17, 2020	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 05, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2023	This missense variant replaces threonine with alanine at codon 268 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 31568572, 32746448, 32826072), cardiomyopathy (PMID: 32746448), long QT syndrome (PMID: 35703482), and in six individuals suspected of having hypertrophic cardiomyopathy (PMID: 30847666). This variant has also been identified in 39/282652 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 18, 2019	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2023	Variant summary: DSC2 c.802A>G (p.Thr268Ala) results in a non-conservative amino acid change located in the Cadherin-like (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251258 control chromosomes (gnomAD). The observed variant frequency is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.802A>G has been reported in the literature in individuals affected with Cardiomyopathy or Long QT Syndrome without strong evidence of causality (Burstein_2021, Kuhnisch_2019, Pena-Pena_2021, Pottinger_2020, Saat_2022), and some patients were repoted to have other co-occurring variants, including a truncating TTN variant. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32826072, 32009526, 31568572, 32746448, 35703482). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 28, 2022

Reported in two pediatric patients with DCM, though both harbored additional disease-related variants; also reported in an adult patient with DCM, though this individual harbored a nonsense variant in the TTN gene (Kuhnisch et al., 2019; Burstein et al., 2021; Pena-Pena et al., 2021); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 34426522, 32746448, 32826072, 31568572) -

Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces threonine with alanine at codon 268 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated individuals affected with dilated cardiomyopathy (PMID: 31568572, 32746448), in another individual affected with cardiomyopathy (PMID: 32746448), and in six individuals suspected of having hypertrophic cardiomyopathy (PMID: 30847666). This variant has also been identified in 39/282652 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2021

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	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.1	D;D;.
REVEL	Uncertain	0.39
Sift	Benign	0.082	T;T;.
Sift4G	Benign	0.21	T;T;.
Polyphen		0.99	D;D;.
Vest4		0.44
MVP		0.71
MPC		0.34
ClinPred		0.12	T
GERP RS		5.6
Varity_R		0.19
gMVP		0.58

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: rs201015785; hg19: chr18-28666679;