rs191143292

Positions:

• chr18-31521193-T-A
• chr18-31521193-T-C
• chr18-31521193-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000261590.13(DSG2):​c.473T>A​(p.Val158Glu) 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. 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. V158G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSG2 ENST00000261590.13 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.83

Genes affected

DSG2 (HGNC:3049): (desmoglein 2) This gene encodes a member of the desmoglein family and cadherin cell adhesion molecule superfamily of proteins. Desmogleins are calcium-binding transmembrane glycoprotein components of desmosomes, cell-cell junctions between epithelial, myocardial, and other cell types. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This gene is present in a gene cluster with other desmoglein gene family members on chromosome 18. Mutations in this gene have been associated with arrhythmogenic right ventricular dysplasia, familial, 10. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.473T>A	p.Val158Glu	missense_variant	5/15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.-62T>A		5_prime_UTR_variant	6/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.473T>A	p.Val158Glu	missense_variant	5/15	1	NM_001943.5	ENSP00000261590	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Benign	0.86
DEOGEN2	Uncertain	0.46	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	T;D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.6	D;.
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.86	P;.
Vest4		0.84
MutPred		0.58		Gain of disorder (P = 0.0108);Gain of disorder (P = 0.0108);
MVP		0.75
MPC		0.53
ClinPred		0.98	D
GERP RS		3.2
Varity_R		0.82
gMVP		0.84

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: rs191143292; hg19: chr18-29101156; COSMIC: COSV55203726;