rs397517402

chr18-31087742-C-Gchr18-31087742-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024422.6(DSC2):c.702G>C(p.Glu234Asp) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E234E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.348

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35717544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.702G>C	p.Glu234Asp	missense_variant	6/16	ENST00000280904.11
DSC2	NM_004949.5	c.702G>C	p.Glu234Asp	missense_variant	6/17
DSC2	NM_001406506.1	c.273G>C	p.Glu91Asp	missense_variant	6/16
DSC2	NM_001406507.1	c.273G>C	p.Glu91Asp	missense_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.702G>C	p.Glu234Asp	missense_variant	6/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.702G>C	p.Glu234Asp	missense_variant	6/17	1
DSC2	ENST00000648081.1	c.273G>C	p.Glu91Asp	missense_variant	7/17
DSC2	ENST00000682357.1	c.273G>C	p.Glu91Asp	missense_variant	6/16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251120 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.0015	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.091	T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.2	N;N;.
REVEL	Benign	0.27
Sift	Benign	0.12	T;T;.
Sift4G	Uncertain	0.014	D;D;.
Polyphen		0.86	P;D;.
Vest4		0.52
MutPred		0.42		Gain of ubiquitination at K232 (P = 0.1181);Gain of ubiquitination at K232 (P = 0.1181);.;
MVP		0.58
MPC		0.40
ClinPred		0.78	D
GERP RS		3.2
Varity_R		0.21
gMVP		0.35

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: rs397517402; hg19: chr18-28667705;