rs3737378

Positions:

• chr18-31524601-C-A

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.828+16C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,609,640 control chromosomes in the GnomAD database, including 56,365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4276 hom., cov: 33)
  • Exomes 𝑓: 0.26 (52089 hom.)
• Consequence: DSG2 NM_001943.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.193

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=-0.91).
• BP6: Variant 18-31524601-C-A is Benign according to our data. Variant chr18-31524601-C-A is described in ClinVar as [Benign]. Clinvar id is 258495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31524601-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.828+16C>A		intron_variant		ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.294+16C>A		intron_variant			XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.828+16C>A		intron_variant		1	NM_001943.5	ENSP00000261590	P1
DSG2	ENST00000682087.2	n.659+16C>A		intron_variant, non_coding_transcript_variant
DSG2	ENST00000683614.2	n.659+16C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34274 AN: 151992 Hom.: 4271 Cov.: 33

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.222

GnomAD3 exomes AF: 0.255 AC: 63014 AN: 246648 Hom.: 8552 AF XY: 0.253 AC XY: 33883 AN XY: 133978

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.293

Gnomad SAS exome AF: 0.226

Gnomad FIN exome AF: 0.335

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.241

GnomAD4 exome AF: 0.263 AC: 383752 AN: 1457530 Hom.: 52089 Cov.: 33 AF XY: 0.262 AC XY: 189805 AN XY: 725248

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.292

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.319

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.254

GnomAD4 genome AF: 0.225 AC: 34283 AN: 152110 Hom.: 4276 Cov.: 33 AF XY: 0.230 AC XY: 17068 AN XY: 74344

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.255

Gnomad4 ASJ AF: 0.176

Gnomad4 EAS AF: 0.293

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.264

Gnomad4 OTH AF: 0.228

Alfa AF: 0.232 Hom.: 808

Bravo AF: 0.217

Asia WGS AF: 0.287 AC: 995 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Arrhythmogenic right ventricular dysplasia 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.99
DANN	Benign	0.32

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: rs3737378; hg19: chr18-29104564;