rs727505205

chr18-31519819-A-Cchr18-31519819-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_001943.5(DSG2):c.98A>C(p.Asn33Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N33S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -0.474

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 Likely_benign. Variant got -6 ACMG points.

PM1

In a propeptide (size 25) in uniprot entity DSG2_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001943.5

BP4

Computational evidence support a benign effect (MetaRNN=0.058069885).

BS2

High AC in GnomAdExome at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.98A>C	p.Asn33Thr	missense_variant	3/15	ENST00000261590.13
DSG2	XM_047437315.1 linkuse as main transcript	c.-437A>C		5_prime_UTR_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DSG2	ENST00000261590.13 linkuse as main transcript	c.98A>C	p.Asn33Thr	missense_variant	3/15	1	NM_001943.5	P1
DSG2	ENST00000683654.1 linkuse as main transcript	c.98A>C	p.Asn33Thr	missense_variant	3/7
DSG2	ENST00000682241.2 linkuse as main transcript	c.98A>C	p.Asn33Thr	missense_variant	3/7
DSG2	ENST00000585206.1 linkuse as main transcript	c.98A>C	p.Asn33Thr	missense_variant	3/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000762

AC:

AN:

249436

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000521

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:

0.000165

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000425

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.0000910

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 25, 2014	The Asn33Thr variant in DSG2 has not been previously reported in individuals wit h cardiomyopathy or in large population studies. Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In s ummary, the clinical significance of the Asn33Thr variant is uncertain. -

Arrhythmogenic right ventricular dysplasia 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 33 of the DSG2 protein (p.Asn33Thr). This variant is present in population databases (rs727505205, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 179897). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2021

The p.N33T variant (also known as c.98A>C), located in coding exon 3 of the DSG2 gene, results from an A to C substitution at nucleotide position 98. This alteration was identified in one patient with dilated cardiomyopathy (DCM) in a large study of pathogenicity of Mendelian variants in cardiomyopathy patients, but clinical details are limited (Walsh R et al. Genet Med, 2017 02;19:192-203). The asparagine at codon 33 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.55

Cadd

Benign

7.1

Dann

Benign

0.50

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.058

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.15

Sift

Benign

0.29

T;.

Sift4G

Benign

0.37

T;D

Polyphen

0.44

B;.

Vest4

0.43

MutPred

0.55

Gain of sheet (P = 0.0011);Gain of sheet (P = 0.0011);

MVP

0.61

MPC

0.097

ClinPred

0.095

GERP RS

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.058

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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