18-31498173-C-G

Position:

• chr18-31498173-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The variant allele was found at a frequency of 0.000931 in 1,194,574 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (0 hom.)
• Consequence: intergenic_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.187

Genes affected

(HGNC:):

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 18-31498173-C-G is Benign according to our data. Variant chr18-31498173-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 326466.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.31498173C>G		intergenic_region
DSG2	NM_001943.5	c.-79C>G		upstream_gene_variant		ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.-651C>G		upstream_gene_variant			XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.-79C>G		upstream_gene_variant		1	NM_001943.5	ENSP00000261590.8
DSG2	ENST00000682241.2	c.-79C>G		upstream_gene_variant				ENSP00000507600.2
DSG2	ENST00000585206.1	c.-79C>G		upstream_gene_variant		2		ENSP00000462503.1

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 258 AN: 151826 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000819 AC: 854 AN: 1042642 Hom.: 0 Cov.: 19 AF XY: 0.000847 AC XY: 418 AN XY: 493496

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000132

Gnomad4 ASJ exome AF: 0.00154

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00922

Gnomad4 NFE exome AF: 0.000663

Gnomad4 OTH exome AF: 0.000728

GnomAD4 genome AF: 0.00170 AC: 258 AN: 151932 Hom.: 1 Cov.: 32 AF XY: 0.00194 AC XY: 144 AN XY: 74280

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0123

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00275 Hom.: 0

Bravo AF: 0.000646

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	DSG2: BS1, BS2 -

Arrhythmogenic right ventricular dysplasia 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.49
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.2

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: rs552915392; hg19: chr18-29078136;