18-31498238-G-GAGGCGA

Position:

• chr18-31498238-G-GAGGCGA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001943.5(DSG2):​c.-13_-8dupAGGCGA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000797 in 1,254,376 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: DSG2 NM_001943.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.838

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.-13_-8dupAGGCGA		5_prime_UTR_variant	1/15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.-585_-580dupAGGCGA		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.-13_-8dupAGGCGA		5_prime_UTR_variant	1/15	1	NM_001943.5	ENSP00000261590.8

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151782 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000635 AC: 7 AN: 1102484 Hom.: 0 Cov.: 30 AF XY: 0.00000382 AC XY: 2 AN XY: 523922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000147

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000323

Gnomad4 OTH exome AF: 0.0000227

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151892 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74270

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 13, 2024

This variant is located in the 5' untranslated region of the DSG2 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSG2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1448121277; hg19: chr18-29078201;