chr18-31546426-G-C

Variant names:

• chr18-31546426-G-C
• rs200830807
• NM_001943.5:c.3040G>C

Variant summary

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

The NM_001943.5(DSG2):​c.3040G>C​(p.Val1014Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V1014I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.50
• Publications: 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	NM_001943.5	MANE Select	c.3040G>C	p.Val1014Leu	missense	Exon 15 of 15	NP_001934.2
	DSG2-AS1	NR_045216.1		n.1346-520C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.3040G>C	p.Val1014Leu	missense	Exon 15 of 15	ENSP00000261590.8
	DSG2	ENST00000713817.1		c.3031G>C	p.Val1011Leu	missense	Exon 16 of 16	ENSP00000519121.1
	DSG2	ENST00000713819.1		c.3031G>C	p.Val1011Leu	missense	Exon 17 of 17	ENSP00000519123.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.027
Eigen_PC	Benign	-0.072
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.078	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.32
MutPred		0.41		Loss of sheet (P = 7e-04)
MVP		0.81
MPC		0.23
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.080
gMVP		0.54
Mutation Taster		=48/52	disease causing

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: rs200830807; hg19: chr18-29126389;