18-31521244-G-C

Position:

chr18-31521244-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP5BS2

The NM_001943.5(DSG2):c.523+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000106 in 1,602,634 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

DSG2
NM_001943.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

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:

DSG2 (HGNC:):

DSG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 18-31521244-G-C is Pathogenic according to our data. Variant chr18-31521244-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188450.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.523+1G>C		splice_donor_variant, intron_variant		ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 linkuse as main transcript	c.-12+1G>C		splice_donor_variant, intron_variant			XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 linkuse as main transcript	c.523+1G>C		splice_donor_variant, intron_variant		1	NM_001943.5	ENSP00000261590.8		Q14126

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150808

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:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000126

AC:

AN:

238030

Hom.:

AF XY:

0.0000232

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:

0.0000721

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000920

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1451740

Hom.:

Cov.:

AF XY:

0.0000180

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:

0.000108

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.0000501

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150894

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73624

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:

0.000210

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 30, 2020

- -

Arrhythmogenic right ventricular dysplasia 10

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

ClinVar contains an entry for this variant (Variation ID: 188450). 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. Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257, 30790397; Invitae). This variant is present in population databases (rs553299589, gnomAD 0.01%). 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). -

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

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Donald Williams Parsons Laboratory, Baylor College of Medicine

Sep 17, 2014

This splice site variant is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was an incidental finding in our study, in a 4-year-old female with mixed neuroglial tumor. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2024

The c.523+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 5 of the DSG2 gene. This variant has been reported in an individual indicated as having arrhythmogenic right ventricular cardiomyopathy, but clinical details were limited (Bourfiss M et al. Circ Genom Precis Med, 2022 Dec;15:e003704). Another alteration affecting this nucleotide (c.523+1G>A) was detected in a cohort referred for arrhythmogenic right ventricular cardiomyopathy (ARVC) genetic testing, and was also detected in a sudden cardiac arrest cohort (Walsh R et al. Genet. Med., 2017 02;19:192-203; Mellor G et al. Circ Cardiovasc Genet, 2017;10:e001686). 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. -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

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

0.32

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