rs794728093

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM4PP3PP5BS2

The NM_001943.5(DSG2):c.829_840delCTTGAAGGGATG(p.Leu277_Met280del) variant causes a conservative inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

DSG2
NM_001943.5 conservative_inframe_deletion, splice_region

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 9.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001943.5.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 18-31524701-AGCTTGAAGGGAT-A is Pathogenic according to our data. Variant chr18-31524701-AGCTTGAAGGGAT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199824.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=5, Pathogenic=1}. Variant chr18-31524701-AGCTTGAAGGGAT-A is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5 link	c.829_840delCTTGAAGGGATG	p.Leu277_Met280del	conservative_inframe_deletion, splice_region_variant	Exon 8 of 15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 link	c.295_306delCTTGAAGGGATG	p.Leu99_Met102del	conservative_inframe_deletion, splice_region_variant	Exon 9 of 16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSG2	ENST00000261590.13 link	c.829-1_839delGCTTGAAGGGAT	p.Leu277fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 8 of 15	1	NM_001943.5	ENSP00000261590.8	Q14126
DSG2	ENST00000682087.2 link	n.660-1_670delGCTTGAAGGGAT		splice_acceptor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 6 of 6				A0A804HLK9
DSG2	ENST00000683614.2 link	n.660-1_670delGCTTGAAGGGAT		splice_acceptor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 6 of 7				A0A804HJ09

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152212

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461834

Hom.:

AF XY:

0.0000275

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:1Uncertain:1

Aug 03, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 12 nucleotides from exon 8 of the DSG2 gene, resulting in an in-frame deletion of 4 amino acids. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 3 unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy and it has been observed to segregate with disease in one of the families (PMID: 17105751, 19279339, 23671136). One of these individuals also carried a pathogenic truncation variant in the PKP2 gene that could explain the observed phenotype (PMID: 23671136). This variant has been identified in 1/280596 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. -

not provided

Pathogenic:1Uncertain:1

Apr 03, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.829_840del12 mutation has been reported as a disease-causing mutation in association with ARVC (Syrris P et al., 2007, Asimaki A et al., 2009). This mutation was present in a parent and child, both of whom met Task Force criteria for the diagnosis of ARVC. Another child from this family with autopsy-confirmed ARVC also harbored this mutation (Syrris P et al., 2007). The mutation was absent from 200 ethnicity-matched control samples in this study. Furthermore, immunohistochemical analysis of cardiac tissue from autopsy in an individual with this mutation showed marked reduction in immunoreactivity for plakophilin2 and desmoplakin when compared to control tissue (Asimaki A et al., 2009). This mutation results in the deletion of 4 amino acids at the beginning of exon 8, that it is predicted to destroy the normal acceptor site of intron 7 and to create a cryptic splice acceptor site in exon 8. In addition, the NHLBI ESP Exome Variant Server reports c.829_840del12 was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, c.829_840del12 in the DSG2 gene is interpreted as a disease-causing mutation. -

Nov 12, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Jul 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 12 nucleotides from exon 8 of the DSG2 gene, resulting in an in-frame deletion of 4 amino acids. Splicing prediction tools suggest that this variant may not disrupt RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported to segregate with arrhythmogenic right ventricular cardiomyopathy in a small family (PMID: 17105751), as well as in two unrelated individuals with this condition (PMID: 19279339, 23671136). One of these individuals also carried a pathogenic truncation variant in the PKP2 gene that could explain the observed phenotype (PMID: 23671136). This variant has been identified in 1/280596 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. -

Arrhythmogenic right ventricular dysplasia 10

Uncertain:1

Jan 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.829_840del, results in the deletion of 4 amino acid(s) of the DSG2 protein (p.Leu277_Met280del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs779260860, gnomAD 0.0008%). This variant has been observed in individual(s) with DSG2-related conditions (PMID: 17105751). This variant is also known as c.829-1delGCTTGAAGGGAT (G277fsX278), 829_840delCTTGAAGGCATG. ClinVar contains an entry for this variant (Variation ID: 199824). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Oct 24, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.829_840del12 variant (also known as p.L277_M280del) is located in coding exon 8 of the DSG2 gene. This variant results from an in-frame CTTGAAGGGATG deletion at nucleotide positions 829 to 840. This results in the deletion of four amino acids between codons 277 and 280. This variant was detected in two related individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), who shared an additional first degree relative with sudden cardiac death due to ARVC, but who did not have genetic testing (Syrris P et al. Eur. Heart J., 2007 Mar;28:581-8). These amino acid positions are generally not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over