rs553299589

chr18-31521244-G-Achr18-31521244-G-Cchr18-31521244-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PP3_StrongPP5

The NM_001943.5(DSG2):c.523+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000131 in 1,451,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DSG2
NM_001943.5 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 6.36

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 Pathogenic. Variant got 13 ACMG points.

PVS1

Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 18-31521244-G-A is Pathogenic according to our data. Variant chr18-31521244-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188446.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=2, Likely_pathogenic=3}. Variant chr18-31521244-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.523+1G>A		splice_donor_variant		ENST00000261590.13
DSG2	XM_047437315.1 linkuse as main transcript	c.-12+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13 linkuse as main transcript	c.523+1G>A		splice_donor_variant		1	NM_001943.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150806

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000420

AC:

AN:

238030

Hom.:

AF XY:

0.00000774

AC XY:

AN XY:

129154

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:

0.0000471

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000131

AC:

AN:

1451740

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

721696

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:

0.0000377

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

150806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73524

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	Reported in individuals with cardiomyopathy (primarily ARVC) and coronary artery disease (CAD)-related sudden cardiac death (SCD) (Walsh et al., 2017; Daoud et al., 2019; Hermida et al., 2019; Vahatalo et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30790397, 28471438, 35087879, 27532257, 31402444, 30731207, 35747619, 36556183, 28600387, 35653365, 37183561) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Aug 11, 2021	- -

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 29, 2016	The c.523+1G>A variant in DSG2 has not been previously reported in individuals with cardiomyopathy or in large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splicing and other truncating variants in the DSG2 gene are established as disease-causing for ARVC. In summary, although additional studies are required to fully establish its clinical significance, the c.523+1G>A variant is likely pathogenic for ARVC. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 03, 2024	This variant causes a G>A nucleotide substitution at the +1 position of intron 5 of the DSG2 gene. Splice prediction tools suggest that this variant may have a significant impact on splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with arrhythmogenic right ventricular cardiomyopathy including one who was homozygous (PMID: 27532257, 28600387, 30790397, ClinVar SCV002569966.1), and in another individual affected with sudden cardiac death with single vessel coronary artery disease and hypertrophied heart (PMID: 35087879). This variant has been identified in 1/238030 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical significance of loss-of-function DSC2 variants in autosomal dominant arrhythmogenic right ventricular cardiomyopathy is not yet clearly established. 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 9

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Sep 08, 2022

We observed a с.523+1G>A genetic variant in the DSG2 gene in a 20-y.o. proband and her 51-y.o. father, both diagnosed with arrhythmogenic right ventricular cardiomyopathy. This variant is not present in LOVD database, not observed at significant frequency in large population cohorts (gnomAD v3.1.2). Online bioinformatic resources classify the с.523+1G>A variant as probably pathogenic. It is expected to result in splice sites changes in mRNA. This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30790397, 28471438, 35087879, 27532257). Due to the fact that our patients were also diagnosed with ARVC, we assume that the с.523+1G>A variant could be classified as Pathogenic. -

Arrhythmogenic right ventricular dysplasia 10

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2023

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 188446). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 20857253, 27532257, 33238575; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 5 of the DSG2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSG2 are known to be pathogenic (PMID: 17105751, 31386562). -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.523+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 5 of the DSG2 gene. This alteration has been reported in cardiomyopathy cohorts, including arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts, as well as a sudden cardiac arrest cohort (Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10; Walsh R et al. Genet Med, 2017 02;19:192-203; Daoud H et al. J Mol Diagn, 2019 05;21:437-448; Hermida A et al. Eur J Heart Fail, 2019 06;21:792-800; Ye JZ et al. Clin Genet, 2019 12;96:506-514). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 11, 2023

This variant causes a G>A nucleotide substitution at the +1 position of intron 5 of the DSG2 gene. Splice prediction tools suggest that this variant may have a significant impact on splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with arrhythmogenic right ventricular cardiomyopathy including one who was homozygous (PMID: 27532257, 28600387, 30790397, ClinVar SCV002569966.1), and in another individual affected with sudden cardiac death with single vessel coronary artery disease and hypertrophied heart (PMID: 35087879). This variant has been identified in 1/238030 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical significance of loss-of-function DSC2 variants in autosomal dominant arrhythmogenic right ventricular cardiomyopathy is not yet clearly established. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.18

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.31

Position offset: -15

DS_DL_spliceai

1.0

Position offset: -1

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