rs3737378

Variant names:

• chr18-31524601-C-A
• rs3737378
• NM_001943.5:c.828+16C>A

Your query was ambiguous. Multiple possible variants found:

• chr18-31524601-C-A
• chr18-31524601-C-G
• chr18-31524601-C-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 10

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1BB

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 258495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001943.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	NM_001943.5	MANE Select	c.828+16C>A		intron	N/A	NP_001934.2	Q14126

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.828+16C>A		intron	N/A	ENSP00000261590.8	Q14126
	DSG2	ENST00000713783.1		c.844C>A	p.Leu282Ile	missense	Exon 7 of 7	ENSP00000519085.1	A0AAQ5BGX2
	DSG2	ENST00000713817.1		c.819+16C>A		intron	N/A	ENSP00000519121.1	A0AAQ5BGZ7

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

GnomAD2 exomes AF: 0.255 AC: 63014 AN: 246648 AF XY: 0.253

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 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

African (AFR) AF: 0.114 AC: 3807 AN: 33344

American (AMR) AF: 0.292 AC: 13058 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4538 AN: 26108

East Asian (EAS) AF: 0.319 AC: 12618 AN: 39544

South Asian (SAS) AF: 0.225 AC: 19327 AN: 86016

European-Finnish (FIN) AF: 0.333 AC: 17765 AN: 53334

Middle Eastern (MID) AF: 0.177 AC: 1017 AN: 5762

European-Non Finnish (NFE) AF: 0.267 AC: 296340 AN: 1108564

Other (OTH) AF: 0.254 AC: 15282 AN: 60202

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

African (AFR) AF: 0.119 AC: 4943 AN: 41516

American (AMR) AF: 0.255 AC: 3901 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 612 AN: 3470

East Asian (EAS) AF: 0.293 AC: 1516 AN: 5170

South Asian (SAS) AF: 0.220 AC: 1060 AN: 4826

European-Finnish (FIN) AF: 0.345 AC: 3634 AN: 10542

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17931 AN: 67982

Other (OTH) AF: 0.228 AC: 483 AN: 2114

Alfa AF: 0.229 Hom.: 817

Bravo AF: 0.217

Asia WGS AF: 0.287 AC: 995 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 10 (1)
-	-	1	Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.99
DANN	Benign	0.32
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3737378;

hg19: chr18-29104564;