rs368512832

Positions:

chr18-31522104-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001943.5(DSG2):c.545A>G(p.Asn182Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 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 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: -1.72

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04102373).

BP6

Variant 18-31522104-A-G is Benign according to our data. Variant chr18-31522104-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44323.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}. Variant chr18-31522104-A-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.545A>G	p.Asn182Ser	missense_variant	6/15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1 linkuse as main transcript	c.11A>G	p.Asn4Ser	missense_variant	7/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 linkuse as main transcript	c.545A>G	p.Asn182Ser	missense_variant	6/15	1	NM_001943.5	ENSP00000261590	P1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249320

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135266

show subpopulations

Gnomad AFR exome

AF:

0.000452

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461560

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000125

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.000539

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000497

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Reported in association with HCM and DCM, including an African American female with infantile-onset DCM who harbored additional disease-related variants (PMID: 24503780, 23396983, 27532257, 31983221); This variant is associated with the following publications: (PMID: 27532257, 31983221, 23396983, 25351510, 30885746, 24503780) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 13, 2016	p.Asn182Ser (c.545A>G) in the DSG2 gene (NM_01943.3) We have seen this in one African-American adult with mild dilated cardiomyopathy and a family history suspicious for familial dilated cardiomyopathy. Given the frequency in the general population, the weak case data, the lack of conservation, and the poor match with the familyâ€™s phenotype, we consider this a variant of uncertain significance, probably benign. The variant has been seen in at least 1 unrelated case of dilated cardiomyopathy (DCM) (not including this patient's family). Pugh et al (2014) identified the variant in a female infant with a clinical diagnosis of DCM who was of â€œBlack or African Americanâ€ ethnicity. Variants in several other genes (TTN, DSP, MYH6, MYL3) were also identified in this patient. No family history or segregation data is available. Per the lab report: â€œThe asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In addition, the serine amino acid residue is found in multiple mammalian species, suggesting that this missense changes does not adversely affect protein function.â€ The variant was seen in 6 of ~60,000 individuals listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 3/10/16). The variant is seen in 5 out of 9798 (AF=0.0005103) African alleles and 1 out of 8612 (AF=0.0001161) East Asian alleles. No other variant at the same codon is listed in this database. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 25, 2019	Variant summary: DSG2 c.545A>G (p.Asn182Ser) results in a conservative amino acid change located in the second cadherin repeat (IPR002126) of the encoded protein sequence, which might affect a potential N-glycosylation site (Debus_2019). Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 280730 control chromosomes, predominantly at a frequency of 0.00058 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 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.545A>G, has been reported in the literature in individuals affected with hypertrophic- or dilated cardiomyopathy, however without strong evidence for causality (Lopes_2013, Pugh_2014, Walsh_2017). In addition, co-occurrence with another pathogenic variant has been reported (TTR c.424G>A, p.Val142Ile; in an internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have cited the variant as uncertain significance (4x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 13, 2015	p.Asn182Ser in exon 6 of DSG2: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, multiple mammals, including cat, dog, rock hyrax, and armadillo, have a seri ne (Ser) at this position despite high nearby amino acid conservation. In additi on, computational prediction tools do not suggest a high likelihood of impact to the protein. This variant has also been identified in 5/9798 African chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs368512832). -

Arrhythmogenic right ventricular dysplasia 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 182 of the DSG2 protein (p.Asn182Ser). This variant is present in population databases (rs368512832, gnomAD 0.05%). This missense change has been observed in individual(s) with dilated or hypertrophic cardiomyopathy (PMID: 23396983, 24503780, 25351510, 31983221). ClinVar contains an entry for this variant (Variation ID: 44323). 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. -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 29, 2019

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.74

CADD

Benign

5.3

DANN

Benign

0.71

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.0090

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.23

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.025

Sift

Benign

0.98

T;.

Sift4G

Benign

0.22

T;T

Polyphen

0.012

B;.

Vest4

0.081

MVP

0.32

MPC

0.060

ClinPred

0.014

GERP RS

-7.3

Varity_R

0.093

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

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