NM_001943.5:c.2318G>A

Variant names:

• chr18-31542836-G-A
• rs2278792
• NM_001943.5:c.2318G>A

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.2318G>A​(p.Arg773Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,376,676 control chromosomes in the GnomAD database, including 55,785 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R773G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.23 (4237 hom., cov: 26)
  • Exomes 𝑓: 0.30 (51548 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.83
• Publications: 40 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026043653).
• BP6: Variant 18-31542836-G-A is Benign according to our data. Variant chr18-31542836-G-A is described in ClinVar as Benign. ClinVar VariationId is 44300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	NM_001943.5	MANE Select	c.2318G>A	p.Arg773Lys	missense	Exon 14 of 15	NP_001934.2
	DSG2-AS1	NR_045216.1		n.1810+266C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSG2	ENST00000261590.13	TSL:1 MANE Select	c.2318G>A	p.Arg773Lys	missense	Exon 14 of 15	ENSP00000261590.8
	DSG2	ENST00000713817.1		c.2309G>A	p.Arg770Lys	missense	Exon 15 of 16	ENSP00000519121.1
	DSG2	ENST00000713819.1		c.2309G>A	p.Arg770Lys	missense	Exon 16 of 17	ENSP00000519123.1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 32204 AN: 140046 Hom.: 4233 Cov.: 26

Gnomad AFR AF: 0.0830

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.223

GnomAD2 exomes AF: 0.265 AC: 53755 AN: 202736 AF XY: 0.264

Gnomad AFR exome AF: 0.0722

Gnomad AMR exome AF: 0.281

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.467

Gnomad FIN exome AF: 0.335

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.249

GnomAD4 exome AF: 0.299 AC: 369845 AN: 1236560 Hom.: 51548 Cov.: 35 AF XY: 0.298 AC XY: 181338 AN XY: 608972

African (AFR) AF: 0.0874 AC: 2101 AN: 24046

American (AMR) AF: 0.311 AC: 9173 AN: 29490

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 3837 AN: 16500

East Asian (EAS) AF: 0.559 AC: 18712 AN: 33484

South Asian (SAS) AF: 0.245 AC: 18050 AN: 73696

European-Finnish (FIN) AF: 0.395 AC: 17016 AN: 43090

Middle Eastern (MID) AF: 0.205 AC: 924 AN: 4502

European-Non Finnish (NFE) AF: 0.296 AC: 285310 AN: 964084

Other (OTH) AF: 0.309 AC: 14722 AN: 47668

GnomAD4 genome AF: 0.230 AC: 32211 AN: 140116 Hom.: 4237 Cov.: 26 AF XY: 0.238 AC XY: 16033 AN XY: 67414

African (AFR) AF: 0.0830 AC: 3097 AN: 37324

American (AMR) AF: 0.283 AC: 3659 AN: 12930

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 605 AN: 3388

East Asian (EAS) AF: 0.476 AC: 2207 AN: 4634

South Asian (SAS) AF: 0.259 AC: 1062 AN: 4098

European-Finnish (FIN) AF: 0.383 AC: 3386 AN: 8844

Middle Eastern (MID) AF: 0.197 AC: 52 AN: 264

European-Non Finnish (NFE) AF: 0.267 AC: 17554 AN: 65814

Other (OTH) AF: 0.230 AC: 447 AN: 1940

Alfa AF: 0.244 Hom.: 16444

Bravo AF: 0.209

TwinsUK AF: 0.263 AC: 974

ALSPAC AF: 0.259 AC: 998

ESP6500AA AF: 0.0778 AC: 307

ESP6500EA AF: 0.254 AC: 2109

ExAC AF: 0.259 AC: 31247

Asia WGS AF: 0.344 AC: 1197 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 07, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33047533)

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Cardiomyopathy Benign:2

Apr 08, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Arrhythmogenic right ventricular dysplasia 10 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Mar 11, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.092
Sift	Benign	0.38	T
Sift4G	Benign	0.31	T
Polyphen		0.026	B
Vest4		0.020
MPC		0.074
ClinPred		0.0055	T
GERP RS		2.2
Varity_R		0.037
gMVP		0.36
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2278792; hg19: chr18-29122799; COSMIC: COSV55203380;