18-31542836-G-C

Position:

• chr18-31542836-G-C

Variant summary

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

The NM_001943.5(DSG2):​c.2318G>C​(p.Arg773Thr) 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. R773K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 26)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83

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]

DSG2-AS1 (HGNC:51311): (DSG2 antisense RNA 1)

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=0.29828024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.2318G>C	p.Arg773Thr	missense_variant	14/15	ENST00000261590.13	NP_001934.2
DSG2-AS1	NR_045216.1	n.1810+266C>G		intron_variant, non_coding_transcript_variant
DSG2	XM_047437315.1	c.1784G>C	p.Arg595Thr	missense_variant	15/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.2318G>C	p.Arg773Thr	missense_variant	14/15	1	NM_001943.5	ENSP00000261590	P1
DSG2-AS1	ENST00000583706.5	n.1848+266C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.039
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.19
Sift	Benign	0.12	T
Sift4G	Uncertain	0.060	T
Polyphen		0.97	D
Vest4		0.31
MutPred		0.48		Loss of helix (P = 0.028);
MVP		0.81
MPC		0.34
ClinPred		0.60	D
GERP RS		2.2
Varity_R		0.053
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2278792; hg19: chr18-29122799;