chr18-31498158-G-C

Variant names:

• chr18-31498158-G-C
• rs149048465
• NM_001943.5:c.-94G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001943.5(DSG2):​c.-94G>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,152,284 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (63 hom.)
• Consequence: DSG2 NM_001943.5 upstream_gene
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.173

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-31498158-G-C is Benign according to our data. Variant chr18-31498158-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 326465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5	c.-94G>C		upstream_gene_variant		ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.-666G>C		upstream_gene_variant			XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.-94G>C		upstream_gene_variant		1	NM_001943.5	ENSP00000261590.8
DSG2	ENST00000683654.1	c.-94G>C		upstream_gene_variant				ENSP00000506971.1
DSG2	ENST00000682241.2	c.-94G>C		upstream_gene_variant				ENSP00000507600.2
DSG2	ENST00000585206.1	c.-94G>C		upstream_gene_variant		2		ENSP00000462503.1

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 700 AN: 151836 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00531

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.0533

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00691

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00814

GnomAD4 exome AF: 0.00356 AC: 3565 AN: 1000340 Hom.: 63 Cov.: 16 AF XY: 0.00364 AC XY: 1726 AN XY: 474024

Gnomad4 AFR exome AF: 0.000433

Gnomad4 AMR exome AF: 0.00574

Gnomad4 ASJ exome AF: 0.00417

Gnomad4 EAS exome AF: 0.0666

Gnomad4 SAS exome AF: 0.00120

Gnomad4 FIN exome AF: 0.00911

Gnomad4 NFE exome AF: 0.00170

Gnomad4 OTH exome AF: 0.00492

GnomAD4 genome AF: 0.00459 AC: 698 AN: 151944 Hom.: 11 Cov.: 32 AF XY: 0.00517 AC XY: 384 AN XY: 74288

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.0533

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00691

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00234 Hom.: 0

Bravo AF: 0.00468

Asia WGS AF: 0.0250 AC: 87 AN: 3464

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.4
DANN	Benign	0.47
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: rs149048465; hg19: chr18-29078121;