chr18-31546681-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001943.5(DSG2):c.3295A>G(p.Thr1099Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,614,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14

Conservation

PhyloP100: 0.0470

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002890557).

BP6

Variant 18-31546681-A-G is Benign according to our data. Variant chr18-31546681-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44314.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=10}. Variant chr18-31546681-A-G is described in Lovd as [Benign]. Variant chr18-31546681-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00128 (195/152268) while in subpopulation AFR AF= 0.00448 (186/41550). AF 95% confidence interval is 0.00395. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 195 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5 link	c.3295A>G	p.Thr1099Ala	missense_variant	Exon 15 of 15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 link	c.2761A>G	p.Thr921Ala	missense_variant	Exon 16 of 16		XP_047293271.1
DSG2-AS1	NR_045216.1 link	n.1346-775T>C		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSG2	ENST00000261590.13 link	c.3295A>G	p.Thr1099Ala	missense_variant	Exon 15 of 15	1	NM_001943.5	ENSP00000261590.8	Q14126
DSG2-AS1	ENST00000583706.5 link	n.1384-775T>C		intron_variant	Intron 3 of 5	5
DSG2-AS1	ENST00000657343.1 link	n.697-775T>C		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

194

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00447

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000297

AC:

AN:

249180

Hom.:

AF XY:

0.000207

AC XY:

AN XY:

135178

show subpopulations

Gnomad AFR exome

AF:

0.00426

Gnomad AMR exome

AF:

0.0000579

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:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000180

AC:

263

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00484

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000585

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.00128

AC:

195

AN:

152268

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00448

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000215

Hom.:

Bravo

AF:

0.00125

ESP6500AA

AF:

0.00399

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000405

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	This variant is associated with the following publications: (PMID: 21636032, 21859740) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DSG2: BP4 -

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

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	DSG2 NM_001943.4 exon 15 p.Thr1099Ala (c.3295A>G): This variant has not been reported in the literature and is present in 0.4% (98/24186) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/18-29126644-A-G). This variant is also present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:44314). This variant amino acid Alanine (Ala) is present in several species including multiple mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 26, 2021	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 24, 2012	Thr1099Ala in exon 15 of DSG2: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (15/3328) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs79068489). Thr1099Ala in exon 15 of DSG2 (r s79068489; allele frequency = 0.5%, 15/3328) ** -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 08, 2020	Variant summary: DSG2 c.3295A>G (p.Thr1099Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 281622 control chromosomes, predominantly at a frequency of 0.0041 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 410 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3295A>G has been reported in the literature in one individual affected with DCM (Garcia-Pavia_2011). The data does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign (1x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as benign. -

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 22, 2020	- -

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	Feb 02, 2025	- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2020

This variant is classified as likely 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

0.063

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.8

DANN

Benign

0.97

DEOGEN2

Benign

0.15

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.52

M_CAP

Benign

0.017

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

REVEL

Benign

0.029

Sift

Benign

0.19

Sift4G

Benign

0.11

Polyphen

0.012

Vest4

0.037

MVP

0.63

MPC

0.072

ClinPred

0.030

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.027

gMVP

0.47

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