chr18-31087710-T-C

Position:

• chr18-31087710-T-C

Variant summary

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

The NM_024422.6(DSC2):​c.734A>G​(p.Glu245Gly) 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:3
• Conservation: PhyloP100: 3.58

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=0.17636663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.734A>G	p.Glu245Gly	missense_variant	6/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.734A>G	p.Glu245Gly	missense_variant	6/17		NP_004940.1
DSC2	NM_001406506.1	c.305A>G	p.Glu102Gly	missense_variant	6/16		NP_001393435.1
DSC2	NM_001406507.1	c.305A>G	p.Glu102Gly	missense_variant	6/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.734A>G	p.Glu245Gly	missense_variant	6/16	1	NM_024422.6	ENSP00000280904	P1
DSC2	ENST00000251081.8	c.734A>G	p.Glu245Gly	missense_variant	6/17	1		ENSP00000251081
DSC2	ENST00000648081.1	c.305A>G	p.Glu102Gly	missense_variant	7/17			ENSP00000497441
DSC2	ENST00000682357.1	c.305A>G	p.Glu102Gly	missense_variant	6/16			ENSP00000507826

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 18, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1172331). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 245 of the DSC2 protein (p.Glu245Gly). -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 14, 2020

This missense variant replaces glutamic acid with glycine at codon 245 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 cardiovascular 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	0.17
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.6	D;D;.
REVEL	Benign	0.12
Sift	Benign	0.39	T;T;.
Sift4G	Benign	0.21	T;T;.
Polyphen		0.038	B;B;.
Vest4		0.39
MutPred		0.50		Loss of catalytic residue at E245 (P = 0.0572);Loss of catalytic residue at E245 (P = 0.0572);.;
MVP		0.74
MPC		0.14
ClinPred		0.43	T
GERP RS		5.0
Varity_R		0.36
gMVP		0.52

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: rs373201722; hg19: chr18-28667673;