rs727502979

Positions:

• chr18-31069139-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.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. 15/21 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: 2.11

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=0.12781212).

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2263G>A	p.Gly755Ser	missense_variant	15/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.2263G>A	p.Gly755Ser	missense_variant	15/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1834G>A	p.Gly612Ser	missense_variant	16/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1834G>A	p.Gly612Ser	missense_variant	15/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 15, 2013	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2014	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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 03, 2023

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 -

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;.
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs727502979; hg19: chr18-28649105;