rs1555638635

Positions:

• chr18-31079910-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000280904.11(DSC2):​c.1600G>A​(p.Asp534Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. D534V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSC2 ENST00000280904.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.19

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.1600G>A	p.Asp534Asn	missense_variant	11/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1600G>A	p.Asp534Asn	missense_variant	11/17		NP_004940.1
DSC2	NM_001406506.1	c.1171G>A	p.Asp391Asn	missense_variant	11/16		NP_001393435.1
DSC2	NM_001406507.1	c.1171G>A	p.Asp391Asn	missense_variant	11/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1600G>A	p.Asp534Asn	missense_variant	11/16	1	NM_024422.6	ENSP00000280904	P1
DSC2	ENST00000251081.8	c.1600G>A	p.Asp534Asn	missense_variant	11/17	1		ENSP00000251081
DSC2	ENST00000648081.1	c.1171G>A	p.Asp391Asn	missense_variant	12/17			ENSP00000497441
DSC2	ENST00000682357.1	c.1171G>A	p.Asp391Asn	missense_variant	11/16			ENSP00000507826

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 534 of the DSC2 protein (p.Asp534Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of DSC2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 468370). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.4	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.8	D;D;.
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.060	T;T;.
Polyphen		1.0	D;D;.
Vest4		0.75
MutPred		0.85		Gain of MoRF binding (P = 0.0581);Gain of MoRF binding (P = 0.0581);.;
MVP		0.85
MPC		0.43
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.78
gMVP		0.94

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: rs1555638635; hg19: chr18-28659876; COSMIC: COSV99199683;