rs200475862

Positions:

• chr18-31071829-C-A
• chr18-31071829-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024422.6(DSC2):​c.1901G>T​(p.Arg634Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R634H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0560

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18404931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.1901G>T	p.Arg634Leu	missense_variant	13/16	ENST00000280904.11
DSC2	NM_004949.5	c.1901G>T	p.Arg634Leu	missense_variant	13/17
DSC2	NM_001406506.1	c.1472G>T	p.Arg491Leu	missense_variant	13/16
DSC2	NM_001406507.1	c.1472G>T	p.Arg491Leu	missense_variant	13/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.1901G>T	p.Arg634Leu	missense_variant	13/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.1901G>T	p.Arg634Leu	missense_variant	13/17	1
DSC2	ENST00000648081.1	c.1472G>T	p.Arg491Leu	missense_variant	14/17
DSC2	ENST00000682357.1	c.1472G>T	p.Arg491Leu	missense_variant	13/16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2016

The p.R634L variant (also known as c.1901G>T), located in coding exon 13 of the DSC2 gene, results from a G to T substitution at nucleotide position 1901. The arginine at codon 634 is replaced by leucine, an amino acid with dissimilar properties. A different alteration affecting this amino acid (p. R634H, c.1901G>A) was previously detected in a patient who reportedly had features of both long QT syndrome and arrhythmogenic right ventricular cardiomyopathy/dysplasia; however, the patient also carried variants in other cardiac-related genes (Tisma-Dupanovic S et al. Ann Noninvasive Electrocardiol. 2013;18:75-8). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), Exome Aggregation Consortium (ExAC), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.080	T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.054
Sift	Benign	0.64	T;T;.
Sift4G	Benign	0.65	T;T;.
Polyphen		0.12	B;B;.
Vest4		0.20
MutPred		0.56		Loss of MoRF binding (P = 0.0101);Loss of MoRF binding (P = 0.0101);.;
MVP		0.53
MPC		0.29
ClinPred		0.83	D
GERP RS		4.3
Varity_R		0.19
gMVP		0.65

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: rs200475862; hg19: chr18-28651795;