rs539821357

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PVS1_StrongPP5BS1_Supporting

The NM_001943.5(DSG2):c.3039C>A(p.Tyr1013*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y1013Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DSG2
NM_001943.5 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5

Conservation

PhyloP100: -2.01

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 links:

DSG2-AS1 (HGNC:51311): (DSG2 antisense RNA 1)

DSG2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.

PP5

Variant 18-31546425-C-A is Pathogenic according to our data. Variant chr18-31546425-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 392196.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000116 (17/1461858) while in subpopulation EAS AF = 0.000403 (16/39700). AF 95% confidence interval is 0.000252. There are 0 homozygotes in GnomAdExome4. There are 9 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DSG2	NM_001943.5 link	c.3039C>A	p.Tyr1013*	stop_gained	Exon 15 of 15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1 link	c.2505C>A	p.Tyr835*	stop_gained	Exon 16 of 16		XP_047293271.1
DSG2-AS1	NR_045216.1 link	n.1346-519G>T		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 link	c.3039C>A	p.Tyr1013*	stop_gained	Exon 15 of 15	1	NM_001943.5	ENSP00000261590.8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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:

0.0000682

AC:

AN:

249368

AF XY:

0.0000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000890

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000403

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111994

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000131

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74464

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000631

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10

Pathogenic:1Uncertain:1

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Arrhythmogenic right ventricular dysplasia 10 (MIM#610193) and Dialted cardiomyopathy 1BB (MIM#612877). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. This gene is usually reported in association with autosomal dominant inheritance with reduced penetrance, however austosomal recessive inheritance has also been observed in more severe cases (OMIM). (I) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of arrhythmogenic right ventricular dysplasia 10 (MIM#610193) and dialted cardiomyopathy 1BB (MIM#612877). (SB) 0601 - Variant is located in the well-established functional domain, desmoglein repeat 5 (Uniprot). It was shown that Dsg unique region (DUR, which contains desmoglein repeat 5) is required for protein stabilization as well as promoting stronger intercellular adhesion (PMID: 23128240). The tyrosine at position 1013 is one of the phosphorylation sites important for the formation of desmosomes and cell adhesion (PMID: 23911551). (SP) 0702 - A few truncation variants downstream to the one identified in this case have strong previous evidence for pathogenicity. These variants have been reported only in patients with Arrhythmogenic right ventricular dysplasia 10 (MIM#610193) but not Dilated cardiomyopathy (MIN#612877) (ClinVar, PMID: 23812740, 21397041, 26296472). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has been previously reported in patients with arrhythmogenic right ventricular dysplasia (ARVD) (ClinVar). It has also been reported as VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Jul 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Tyr1013*) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 106 amino acid(s) of the DSG2 protein. This variant is present in population databases (rs539821357, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 392196). This variant disrupts a region of the DSG2 protein in which other variant(s) (p.Glu1020Alafs*18) have been determined to be pathogenic (PMID: 20864495, 21397041, 23381804). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Cardiomyopathy

Uncertain:2

Mar 22, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant changes 1 nucleotide in exon 15 of the DSG2 gene, creating a premature translation stop signal in the last coding exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 34500006). This variant has been identified in 18/280770 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Nov 30, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB

Pathogenic:1

Apr 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Jul 21, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation as the last 106 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 31931689, 31983221, 34500006, 36129056, 35288587)

Cardiovascular phenotype

Uncertain:1

Mar 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Y1013* variant (also known as c.3039C>A), located in coding exon 15 of the DSG2 gene, results from a C to A substitution at nucleotide position 3039. This changes the amino acid from a tyrosine to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theDSG2 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 9% of the protein. The exact functional effect of this alteration is unknown. Additionally, based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Benign

0.91

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.96

PhyloP100

-2.0

Vest4

0.80

GERP RS

-4.6

Mutation Taster

=7/193

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over