NM_001943.5:c.217-5G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001943.5(DSG2):c.217-5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,613,172 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 35 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 27 hom. )

Consequence

DSG2
NM_001943.5 splice_region, intron

Scores

Splicing: ADA: 0.0003975

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.01

Publications

2 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

DSG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 18-31520798-G-T is Benign according to our data. Variant chr18-31520798-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1738/152186) while in subpopulation AFR AF = 0.0398 (1652/41508). AF 95% confidence interval is 0.0382. There are 35 homozygotes in GnomAd4. There are 806 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AD,AR gene

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.217-5G>T		splice_region intron	N/A	NP_001934.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DSG2	ENST00000261590.13	TSL:1 MANE Select	c.217-5G>T	splice_region intron	N/A	ENSP00000261590.8
DSG2	ENST00000713817.1		c.208-5G>T	splice_region intron	N/A	ENSP00000519121.1
DSG2	ENST00000713819.1		c.208-5G>T	splice_region intron	N/A	ENSP00000519123.1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1728

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0397

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00284

AC:

707

AN:

248982

AF XY:

0.00215

show subpopulations

Gnomad AFR exome

AF:

0.0408

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000885

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00110

AC:

1612

AN:

1460986

Hom.:

Cov.:

AF XY:

0.000915

AC XY:

665

AN XY:

726806

show subpopulations

African (AFR)

AF:

0.0411

AC:

1372

AN:

33422

American (AMR)

AF:

0.00177

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.000700

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0000261

AC:

AN:

1111534

Other (OTH)

AF:

0.00207

AC:

125

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

140

209

279

349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0114

AC:

1738

AN:

152186

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

806

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0398

AC:

1652

AN:

41508

American (AMR)

AF:

0.00425

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68010

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

175

262

350

437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00465

Hom.:

Bravo

AF:

0.0129

Asia WGS

AF:

0.00404

AC:

AN:

3476

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 24, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

217-5G>T in Intron 3 of DSG2: This variant is not expected to have clinical sign ificance because it is not located within the +/- 1,2 invariant region. It has b een identified in 2.8% (111/2898) of African American chromosomes from a broad p opulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; rs80073511).

Apr 28, 2014

GeneDx

Significance: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.

Arrhythmogenic right ventricular dysplasia 10

Benign:2

Feb 03, 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:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

not provided

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiomyopathy

Benign:1

Jun 11, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Jun 25, 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

BayesDel_noAF

Benign

-0.75

CADD

Benign

8.9

(source)

DANN

Benign

0.52

PhyloP100

1.0

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00040

dbscSNV1_RF

Benign

0.12

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over