rs727502979

Variant names:

• chr18-31069139-C-T
• rs727502979
• NM_024422.6:c.2263G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024422.6(DSC2):​c.2263G>A​(p.Gly755Ser) 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. 16/22 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. G755V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.11
• Publications: 1 publications found

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]

DSC2 Gene-Disease associations (from GenCC):

• familial isolated arrhythmogenic right ventricular dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 11

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12781212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2263G>A	p.Gly755Ser	missense_variant	Exon 15 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2263G>A	p.Gly755Ser	missense_variant	Exon 15 of 17		NP_004940.1
DSC2	NM_001406506.1	c.1834G>A	p.Gly612Ser	missense_variant	Exon 15 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.1834G>A	p.Gly612Ser	missense_variant	Exon 15 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2263G>A	p.Gly755Ser	missense_variant	Exon 15 of 16	1	NM_024422.6	ENSP00000280904.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Oct 28, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly755Ser variant in DSC2 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction too ls and conservation analysis suggest that this variant may not impact the protei n, though this information is not predictive enough to rule out pathogenicity. I n summary, the clinical significance of the p.Gly755Ser variant is uncertain. -

Nov 15, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the lack of case data we consider this a variant of uncertain significance. The variant is novel. The variant has not been reported in individuals with cardiomyopathy or in large population studies and multiple computational prediction tool suggest the variant may not impact the protein. -

not provided Uncertain:1

Feb 03, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype Uncertain:1

May 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G755S variant (also known as c.2263G>A), located in coding exon 15 of the DSC2 gene, results from a G to A substitution at nucleotide position 2263. The glycine at codon 755 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.048	T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.5	M;M;.
PhyloP100		2.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N;N;.
REVEL	Benign	0.12
Sift	Benign	0.55	T;T;.
Sift4G	Benign	0.31	T;T;.
Polyphen		0.45	B;P;.
Vest4		0.070
MutPred		0.39		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;
MVP		0.67
MPC		0.18
ClinPred		0.16	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.57
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727502979; hg19: chr18-28649105;