Variant rs727502987 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_SupportingBS2

The NM_001943.5(DSG2):c.1038_1040delGAA(p.Lys346del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000052 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

DSG2
NM_001943.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 6.39

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001943.5. Strenght limited to Supporting due to length of the change: 1aa.

BS2

High AC in GnomAdExome4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5 link	c.1038_1040delGAA	p.Lys346del	disruptive_inframe_deletion	9/15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 link	c.504_506delGAA	p.Lys168del	disruptive_inframe_deletion	10/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 link	c.1038_1040delGAA	p.Lys346del	disruptive_inframe_deletion	9/15	1	NM_001943.5	ENSP00000261590.8		Q14126
DSG2	ENST00000683614.2 link	n.869_871delGAA		non_coding_transcript_exon_variant	7/7					A0A804HJ09

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152186

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

249096

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135156

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461678

Hom.:

AF XY:

0.0000523

AC XY:

AN XY:

727130

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:

0.0000701

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are reported mechanisms of disease in this gene and are associated with arrhythmogenic right ventricular dysplasia 10 (ARVD; MIM#610193) and dilated cardiomyopathy 1BB (DCM; MIM#612877) (ClinVar, PMID: 23071725). (I) 0108 - This gene is associated with both recessive and dominant disease. It is commonly associated to dominant inheritance; however, recessive has been reported in severe DCM patients (OMIM). (I) 0112 - The ARVD condition associated with this gene has incomplete penetrance (OMIM). (I) 0216 - In-frame insertion/deletion in a non-repetitive region that has moderate conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 and v3 non-v2: 6 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated cadherin domain (DECIPHER). (I) 0705 - No comparable in-frame deletion variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported by multiple clinical laboratories as VUS (ClinVar). It has also been reported in nine individuals with ARVC/D, three of whom also have a frameshift or splice variant in DSG2 (cardiodb and PMIDs: 27532257, 20857253, 21606390, 25820315, 36357925, 37418234). In addition, this variant has been reported in an individual with nonischemic DCM and ventricular tachycardia, who also has a frameshift variant in the TTN gene (PMID: 33190517). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Immunostaining of buccal mucosa cells from a patient with this variant showed the signal for plakoglobin was diminished or absent (PMID: 26850880). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	This variant, c.1038_1040del, results in the deletion of 1 amino acid(s) of the DSG2 protein (p.Lys346del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs727502987, gnomAD 0.002%). This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20857253, 21606390, 27532257). ClinVar contains an entry for this variant (Variation ID: 163205). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 19, 2014

The Lys346del variant in DSG2 has been reported in 2 individuals with ARVC and w as absent from 1400 control chromosomes (Tan 2010, Quarta 2011). In addition, th is variant has been identified by our laboratory in 1 individual with HCM (LMM u npublished data). Two of these individuals (Tan 2010, LMM) carried other likely pathogenic variants, including 1 in the DSG2 gene on the other allele (in trans) . This variant is a deletion of 1 amino acid at position 346 and is not predicte d to alter the protein reading-frame, though it is unclear if this deletion will impact the protein. In summary, the clinical significance of the Lys346del vari ant is uncertain. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 07, 2023

This variant results in a deletion of single amino acid at codon 346 position of the DSG2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606390, 27532257, 29759408). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy in trans with a pathogenic DSG2 c.523+2T>C variant, which could explain the observed phenotype (PMID: 20857253, 29759408). This variant has been identified in 2/249096 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 cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Feb 02, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of one amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 23810894, 20857253, 23871885, 23671136, 24563469, 27532257, 31402444, 31386562, 33190517, 21606390, 29759408, 32114801, 24585727) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2021

The c.1038_1040delGAA variant (also known as p.K346del) is located in coding exon 9 of the DSG2 gene. This variant results from an in-frame GAA deletion at nucleotide positions 1038 to 1040. This results in the in-frame deletion of a lysine at codon 346. This variant has been identified in individuals with arrhythmogenic right ventricular cardiomyopathy, some of whom had additional cardiac variants detected (Tan BY et al. J Cardiovasc Transl Res, 2010 Dec;3:663-73; Quarta G et al. Circulation, 2011 Jun;123:2701-9; Bhonsale A et al. Circ Arrhythm Electrophysiol, 2013 Jun;6:569-78; Orgeron GM et al. J Am Heart Assoc, 2017 Jun;6). This amino acid position is 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). Based on available evidence to date, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

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