rs761796202

Positions:

• chr18-31086638-G-C
• chr18-31086638-G-T

Variant summary

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

The NM_024422.6(DSC2):​c.880C>G​(p.Leu294Val) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L294I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.583

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=0.3737016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.880C>G	p.Leu294Val	missense_variant	7/16	ENST00000280904.11
DSC2	NM_004949.5	c.880C>G	p.Leu294Val	missense_variant	7/17
DSC2	NM_001406506.1	c.451C>G	p.Leu151Val	missense_variant	7/16
DSC2	NM_001406507.1	c.451C>G	p.Leu151Val	missense_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.880C>G	p.Leu294Val	missense_variant	7/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.880C>G	p.Leu294Val	missense_variant	7/17	1
DSC2	ENST00000648081.1	c.451C>G	p.Leu151Val	missense_variant	8/17
DSC2	ENST00000682357.1	c.451C>G	p.Leu151Val	missense_variant	7/16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N;N;.
REVEL	Benign	0.11
Sift	Benign	0.13	T;T;.
Sift4G	Benign	0.34	T;T;.
Polyphen		0.95	P;P;.
Vest4		0.15
MutPred		0.49		Gain of glycosylation at S291 (P = 0.0683);Gain of glycosylation at S291 (P = 0.0683);.;
MVP		0.56
MPC		0.33
ClinPred		0.45	T
GERP RS		-1.4
Varity_R		0.093
gMVP		0.46

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: rs761796202; hg19: chr18-28666601;