rs150864240

Positions:

chr18-31546468-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001943.5(DSG2):c.3082G>A(p.Gly1028Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,614,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.471

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:):

DSG2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003566116).

BP6

Variant 18-31546468-G-A is Benign according to our data. Variant chr18-31546468-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 163221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31546468-G-A is described in Lovd as [Benign]. Variant chr18-31546468-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00181 (276/152330) while in subpopulation AFR AF= 0.00654 (272/41578). AF 95% confidence interval is 0.0059. There are 0 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 276 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.3082G>A	p.Gly1028Ser	missense_variant	15/15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 linkuse as main transcript	c.2548G>A	p.Gly850Ser	missense_variant	16/16		XP_047293271.1
DSG2-AS1	NR_045216.1 linkuse as main transcript	n.1346-562C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSG2	ENST00000261590.13 linkuse as main transcript	c.3082G>A	p.Gly1028Ser	missense_variant	15/15	1	NM_001943.5	ENSP00000261590.8	Q14126
DSG2-AS1	ENST00000583706.5 linkuse as main transcript	n.1384-562C>T		intron_variant		5
DSG2-AS1	ENST00000657343.1 linkuse as main transcript	n.697-562C>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00182

AC:

277

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00659

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000445

AC:

111

AN:

249442

Hom.:

AF XY:

0.000288

AC XY:

AN XY:

135322

show subpopulations

Gnomad AFR exome

AF:

0.00658

Gnomad AMR exome

AF:

0.000203

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:

0.00

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000181

AC:

264

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

104

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00636

Gnomad4 AMR exome

AF:

0.000291

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:

0.00000270

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.00181

AC:

276

AN:

152330

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

133

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00654

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000366

Hom.:

Bravo

AF:

0.00213

ESP6500AA

AF:

0.00491

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000628

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 23, 2015	p.Gly1028Ser in exon 15 of DSG2: This variant is not expected to have clinical s ignificance because it has been identified in 0.7% (72/9808) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs150864240). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 15, 2018	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2020	- -

Arrhythmogenic right ventricular dysplasia 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DSG2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.56

DEOGEN2

Benign

0.22

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.70

M_CAP

Benign

0.041

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.92

REVEL

Benign

0.067

Sift

Benign

0.52

Sift4G

Benign

0.13

Polyphen

0.087

Vest4

0.065

MVP

0.62

MPC

0.074

ClinPred

0.00020

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.020

gMVP

0.33

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

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