18-31498197-G-C

Position:

• chr18-31498197-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001943.5(DSG2):​c.-55G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,226,226 control chromosomes in the GnomAD database, including 8 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: 0.0023 (7 hom.)
• Consequence: DSG2 NM_001943.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.766

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-31498197-G-C is Benign according to our data. Variant chr18-31498197-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 326467.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chr18-31498197-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0017 (259/151972) while in subpopulation NFE AF= 0.00283 (192/67926). AF 95% confidence interval is 0.0025. There are 1 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 259 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.-55G>C		5_prime_UTR_variant	1/15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.-627G>C		5_prime_UTR_variant	1/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590	c.-55G>C		5_prime_UTR_variant	1/15	1	NM_001943.5	ENSP00000261590.8
DSG2	ENST00000683654.1	c.-55G>C		upstream_gene_variant				ENSP00000506971.1
DSG2	ENST00000682241.2	c.-55G>C		upstream_gene_variant				ENSP00000507600.2
DSG2	ENST00000585206.1	c.-55G>C		upstream_gene_variant		2		ENSP00000462503.1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 259 AN: 151864 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000798

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00283

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00230 AC: 2471 AN: 1074254 Hom.: 7 Cov.: 30 AF XY: 0.00233 AC XY: 1184 AN XY: 508498

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.00427

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000513

Gnomad4 FIN exome AF: 0.000479

Gnomad4 NFE exome AF: 0.00252

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00170 AC: 259 AN: 151972 Hom.: 1 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74308

Gnomad4 AFR AF: 0.000795

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.00283

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.00179

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.5
DANN	Benign	0.46
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: rs551539015; hg19: chr18-29078160;