chr18-31542861-G-A

Variant names:

• chr18-31542861-G-A
• rs776516070
• NM_001943.5:c.2334+9G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001943.5(DSG2):​c.2334+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000401 in 1,123,480 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000049 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: DSG2 NM_001943.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0120
• Publications: 0 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-31542861-G-A is Benign according to our data. Variant chr18-31542861-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377805.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000495 (7/141538) while in subpopulation AMR AF = 0.000514 (7/13612). AF 95% confidence interval is 0.000241. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5	c.2334+9G>A		intron_variant	Intron 14 of 14	ENST00000261590.13	NP_001934.2
DSG2-AS1	NR_045216.1	n.1810+241C>T		intron_variant	Intron 5 of 5
DSG2	XM_047437315.1	c.1800+9G>A		intron_variant	Intron 15 of 15		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.2334+9G>A		intron_variant	Intron 14 of 14	1	NM_001943.5	ENSP00000261590.8

Frequencies

GnomAD3 genomes AF: 0.0000495 AC: 7 AN: 141444 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000515

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000185 AC: 33 AN: 178566 AF XY: 0.000209

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000244

GnomAD4 exome AF: 0.0000387 AC: 38 AN: 981942 Hom.: 0 Cov.: 23 AF XY: 0.0000470 AC XY: 23 AN XY: 488944

African (AFR) AF: 0.00 AC: 0 AN: 18754

American (AMR) AF: 0.00138 AC: 37 AN: 26890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13782

East Asian (EAS) AF: 0.00 AC: 0 AN: 32958

South Asian (SAS) AF: 0.00 AC: 0 AN: 60104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3972

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 743714

Other (OTH) AF: 0.0000252 AC: 1 AN: 39692

GnomAD4 genome AF: 0.0000495 AC: 7 AN: 141538 Hom.: 0 Cov.: 27 AF XY: 0.0000587 AC XY: 4 AN XY: 68192

African (AFR) AF: 0.00 AC: 0 AN: 37908

American (AMR) AF: 0.000514 AC: 7 AN: 13612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 4596

South Asian (SAS) AF: 0.00 AC: 0 AN: 4142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66100

Other (OTH) AF: 0.00 AC: 0 AN: 1934

Alfa AF: 0.0000440 Hom.: 0

Bravo AF: 0.0000945

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10 Uncertain:1 Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, 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 specified Benign:1

Jul 06, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

DSG2-related disorder Benign:1

Oct 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.3
DANN	Benign	0.67
PhyloP100		-0.012

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: rs776516070; hg19: chr18-29122824;