18-31071816-C-G

Position:

• chr18-31071816-C-G

Variant summary

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

The NM_024422.6(DSC2):​c.1914G>C​(p.Gln638His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000352 in 1,613,820 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (3 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 0.121

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=0.005548209).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000387 (59/152308) while in subpopulation AFR AF= 0.000625 (26/41576). AF 95% confidence interval is 0.000438. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.1914G>C	p.Gln638His	missense_variant	13/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1914G>C	p.Gln638His	missense_variant	13/17		NP_004940.1
DSC2	NM_001406506.1	c.1485G>C	p.Gln495His	missense_variant	13/16		NP_001393435.1
DSC2	NM_001406507.1	c.1485G>C	p.Gln495His	missense_variant	13/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1914G>C	p.Gln638His	missense_variant	13/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.1914G>C	p.Gln638His	missense_variant	13/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1485G>C	p.Gln495His	missense_variant	14/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1485G>C	p.Gln495His	missense_variant	13/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000543 AC: 136 AN: 250554 Hom.: 0 AF XY: 0.000583 AC XY: 79 AN XY: 135420

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00657

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000348 AC: 509 AN: 1461512 Hom.: 3 Cov.: 31 AF XY: 0.000384 AC XY: 279 AN XY: 727064

Gnomad4 AFR exome AF: 0.000897

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00566

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000157

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74464

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000518 Hom.: 0

Bravo AF: 0.000400

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2020	This variant is associated with the following publications: (PMID: 21606396, 23861362, 20031617, 20716751, 20152563, 20857253, 20829228) -
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+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DSC2: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2020	Variant summary: DSC2 c.1914G>C (p.Gln638His) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 252554 control chromosomes, predominantly at a frequency of 0.00069 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 28 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 a benign polymorphism found primarily in populations of South Asian origin. c.1914G>C has been reported in the literature in individuals affected with Dilated Cardiomyopathy (DCM) and Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC, Elliott_2010, Xu_2010). These report(s) 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=5). Based on the evidence outlined above, the variant was re-classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 10, 2015	The p.Gln638His variant in DSC2 has been reported in at least 4 individuals with a range of phenotypes (DCM, ARVD/C, HCM) (Elliot 2010, Cox 2011, LMM unpublishe d data). This variant has been identified in 0.1% (11/16342) of South Asian chr omosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org; db SNP rs147742157) and once in another control population in the literature (Den H aan 2009). Computational prediction tools and conservation analysis suggest that the p.Gln638His variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical signif icance of the p.Gln638His variant is uncertain. -

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 05, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 05, 2018	- -

DSC2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2023

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). -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Mar 12, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 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	0.25
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Benign	0.041
Sift	Benign	0.19	T;T;.
Sift4G	Benign	0.14	T;D;.
Polyphen		0.0070	B;B;.
Vest4		0.25
MutPred		0.43		Gain of methylation at R634 (P = 0.0694);Gain of methylation at R634 (P = 0.0694);.;
MVP		0.57
MPC		0.16
ClinPred		0.0075	T
GERP RS		-0.20
Varity_R		0.14
gMVP		0.55

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: rs147742157; hg19: chr18-28651782;