18-31545746-A-C

Variant names:

• chr18-31545746-A-C
• rs369868954
• NM_001943.5:c.2360A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001943.5(DSG2):​c.2360A>C​(p.Asp787Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. D787G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001943.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	NM_001943.5	MANE Select	c.2360A>C	p.Asp787Ala	missense	Exon 15 of 15	NP_001934.2	Q14126
	DSG2-AS1	NR_045216.1		n.1506T>G		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.2360A>C	p.Asp787Ala	missense	Exon 15 of 15	ENSP00000261590.8	Q14126
	DSG2	ENST00000713817.1		c.2351A>C	p.Asp784Ala	missense	Exon 16 of 16	ENSP00000519121.1	A0AAQ5BGZ7
	DSG2	ENST00000713819.1		c.2351A>C	p.Asp784Ala	missense	Exon 17 of 17	ENSP00000519123.1	A0AAQ5BGZ7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.074	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.7
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.29
MutPred		0.28		Loss of solvent accessibility (P = 0.0595)
MVP		0.89
MPC		0.37
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.35
gMVP		0.70
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs369868954; hg19: chr18-29125709;