rs1060502992

Positions:

• chr18-31087672-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.772G>A​(p.Val258Met) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.71

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=0.25849065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.772G>A	p.Val258Met	missense_variant	6/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.772G>A	p.Val258Met	missense_variant	6/17		NP_004940.1
DSC2	NM_001406506.1	c.343G>A	p.Val115Met	missense_variant	6/16		NP_001393435.1
DSC2	NM_001406507.1	c.343G>A	p.Val115Met	missense_variant	6/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.772G>A	p.Val258Met	missense_variant	6/16	1	NM_024422.6	ENSP00000280904	P1
DSC2	ENST00000251081.8	c.772G>A	p.Val258Met	missense_variant	6/17	1		ENSP00000251081
DSC2	ENST00000648081.1	c.343G>A	p.Val115Met	missense_variant	7/17			ENSP00000497441
DSC2	ENST00000682357.1	c.343G>A	p.Val115Met	missense_variant	6/16			ENSP00000507826

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 08, 2018

This sequence change replaces valine with methionine at codon 258 of the DSC2 protein (p.Val258Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DSC2-related disease. -

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

May 15, 2023

This missense variant replaces valine with methionine at codon 258 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 not been reported in individuals affected with DSC2-related disorders in the literature. This variant has not been identified 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.73	N;N;.
REVEL	Benign	0.18
Sift	Benign	0.21	T;T;.
Sift4G	Benign	0.21	T;T;.
Polyphen		0.84	P;P;.
Vest4		0.39
MutPred		0.61		Loss of stability (P = 0.1582);Loss of stability (P = 0.1582);.;
MVP		0.53
MPC		0.39
ClinPred		0.34	T
GERP RS		-4.3
Varity_R		0.13
gMVP		0.31

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: rs1060502992; hg19: chr18-28667635;