18-31521157-G-T

Position:

• chr18-31521157-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5 BP6 BS2

The NM_001943.5(DSG2):​c.437G>T​(p.Arg146Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00078 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R146H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (0 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:14 O:1
• Conservation: PhyloP100: 2.56

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31521157-G-A is described in Lovd as [Likely_pathogenic].
• BP6: Variant 18-31521157-G-T is Benign according to our data. Variant chr18-31521157-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44317.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=4, not_provided=1}. Variant chr18-31521157-G-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5	c.437G>T	p.Arg146Leu	missense_variant	5/15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.-98G>T		5_prime_UTR_variant	6/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.437G>T	p.Arg146Leu	missense_variant	5/15	1	NM_001943.5	ENSP00000261590.8

Frequencies

GnomAD3 genomes AF: 0.000579 AC: 88 AN: 151956 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

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: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000393 AC: 98 AN: 249344 Hom.: 0 AF XY: 0.000347 AC XY: 47 AN XY: 135278

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000760

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000801 AC: 1171 AN: 1461746 Hom.: 0 Cov.: 33 AF XY: 0.000781 AC XY: 568 AN XY: 727176

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000579 AC: 88 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74326

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.000465

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00109 AC: 9

ExAC AF: 0.000306 AC: 37

EpiCase AF: 0.000927

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:14 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:8 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2023	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2024	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 21, 2009	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2024	Variant summary: DSG2 c.437G>T (p.Arg146Leu) results in a non-conservative amino acid change located in the Cadherin-like domain (Cadherin-like) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 249344 control chromosomes, predominantly at a frequency of 0.00076 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00025). c.437G>T has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Mellor_2017, Nagyova_2023, Fressart_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Co-occurrence with another pathogenic variant has been reported in one individual with Arrhythmogenic Right Ventricular Cardiomyopathy (PKP2 c.235C>T, p.Arg79X) (Nagyova_2023), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 20400443, 28600387, 37418234). ClinVar contains an entry for this variant (Variation ID: 44317). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 25, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the information reviewed below, we classify it as a variant of unknown significance. This variant has previously been reported in one proband with ARVC who also carried a premature stop codon in PKP2, and the DSG2 variant was categorized as a variant of unknown significance (Fressart et al. 2010). There is no published segregation data. This is a non-conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Leucine. The Arginine at this location is highly conserved across mammalian species, but it is a Proline in birds and the amino acid varies across fish species. This variant is in the cadherin domain. Variation at nearby residues has been associated with ARVC, which may support the functional importance of this region of the protein: Val149Phe, Asp154Glu (HGMD professional version as of January 17, 2014). Kapplinger et al. have proposed a “hot spot” for DSG2 variants between amino acids 24-388 in patients with ARVC but not in controls. This variant does fall within that hot spot. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 0.983. In total the variant has been seen in 9 out of over 60,000 published controls and individuals from publicly available population datasets. This variant is present in 9 Caucasian individuals in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4100 Caucasian and ~1900 African American individuals. Furthermore, a Arg146Cys variant at the same amino acid is present in one African-American individual. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. The variant is present in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) as rs113451409, submitted by 6 different sequencing projects or labs. It is not present in 1000 Genomes (http://browser.1000genomes.org/index.htm) as of 1/26/2015. The variant was not observed in published controls: 300 Caucasian controls (Fressart et al. 2010). There are 37 individuals in ExAc with this variant and, of these, 1 of them is Latino, 2 are African, 1 is “other”, and 33 are Caucasian. -

Arrhythmogenic right ventricular dysplasia 10 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0103 - Loss of function and gain of function are reported mechanisms of disease in this gene and are associated with arrhythmogenic right ventricular dysplasia 10 (ARVD; MIM#610193) and dilated cardiomyopathy 1BB (DCM; MIM#612877) (ClinVar, PMID: 23071725). (I) 0108 - This gene is associated with both recessive and dominant disease. It is commonly associated to dominant inheritance, however recessive has been reported in severe DCM patients (OMIM). (I) 0112 - The ARVD condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to leucine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of arrhythmogenic right ventricular dysplasia 10 (MIM#610193) and dilated cardiomyopathy 1BB (MIM#612877). (SB) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD v2 (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cadherin domain (NCBI, Uniprot). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. p.(Arg146His) has been reported as likely benign (LOVD) and VUS (LOVD, ClinVar) in a clinical setting. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported as likely benign and VUS (LOVD, ClinVar, PMID: 23861362). In addition, it has been described as a VUS in an individual with ARVC who also harboured a pathogenic variant in PKP2 (PMID: 20400443) and in an individual with idiopathic sudden cardiac arrest (PMID: 28600387). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 14, 2023	- -

Cardiac arrest Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Apr 27, 2015

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Oct 30, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 2020

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	Uncertain	0.41
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.79
DEOGEN2	Uncertain	0.43	T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.014	D;.
Sift4G	Uncertain	0.027	D;T
Polyphen		0.98	D;.
Vest4		0.67
MVP		0.66
MPC		0.40
ClinPred		0.11	T
GERP RS		4.8
Varity_R		0.31
gMVP		0.77

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

Other links and lift over

dbSNP: rs113451409; hg19: chr18-29101120;