rs16962093

Positions:

chr18-31545973-A-C

Variant summary

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

The NM_001943.5(DSG2):c.2587A>C(p.Met863Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,206 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 18 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 7 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -1.52

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:51311): (DSG2 antisense RNA 1)

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=0.0027729273).

BP6

Variant 18-31545973-A-C is Benign according to our data. Variant chr18-31545973-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 44304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31545973-A-C is described in Lovd as [Benign]. Variant chr18-31545973-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00648 (987/152348) while in subpopulation AFR AF= 0.0225 (935/41578). AF 95% confidence interval is 0.0213. There are 18 homozygotes in gnomad4. There are 455 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 987 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSG2	NM_001943.5 linkuse as main transcript	c.2587A>C	p.Met863Leu	missense_variant	15/15	ENST00000261590.13	NP_001934.2
DSG2-AS1	NR_045216.1 linkuse as main transcript	n.1346-67T>G		intron_variant, non_coding_transcript_variant
DSG2	XM_047437315.1 linkuse as main transcript	c.2053A>C	p.Met685Leu	missense_variant	16/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DSG2	ENST00000261590.13 linkuse as main transcript	c.2587A>C	p.Met863Leu	missense_variant	15/15	1	NM_001943.5	ENSP00000261590	P1
DSG2-AS1	ENST00000583706.5 linkuse as main transcript	n.1384-67T>G		intron_variant, non_coding_transcript_variant		5
DSG2-AS1	ENST00000657343.1 linkuse as main transcript	n.697-67T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00640

AC:

975

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0223

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

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:

0.0000441

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00165

AC:

409

AN:

248428

Hom.:

AF XY:

0.00126

AC XY:

170

AN XY:

134858

show subpopulations

Gnomad AFR exome

AF:

0.0232

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000534

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000626

AC:

915

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000545

AC XY:

396

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0212

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.00167

GnomAD4 genome

AF:

0.00648

AC:

987

AN:

152348

Hom.:

Cov.:

AF XY:

0.00611

AC XY:

455

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.0225

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00112

Hom.:

Bravo

AF:

0.00723

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0221

AC:

ESP6500EA

AF:

0.000244

AC:

ExAC

AF:

0.00195

AC:

236

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 17, 2012	Met863Leu in exon 15 of DSG2: This variant is not expected to have clinical sign ificance because it has been identified in 2.1% (63/3012) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs16962093). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 11, 2018	- -

Arrhythmogenic right ventricular dysplasia 10

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 03, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 29, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2015

This alteration is classified as benign based on a combination of the following: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.0030

DANN

Benign

0.71

DEOGEN2

Benign

0.084

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.95

MutationTaster

Benign

1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.16

REVEL

Benign

0.071

Sift

Benign

0.79

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.053

MutPred

0.16

Gain of glycosylation at S862 (P = 0.0905);

MVP

0.26

MPC

0.067

ClinPred

0.0056

GERP RS

-12

Varity_R

0.043

gMVP

0.15

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