18-31538880-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001943.5(DSG2):c.1781T>C(p.Leu594Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,614,194 control chromosomes in the GnomAD database, including 2 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). Synonymous variant affecting the same amino acid position (i.e. L594L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 1.85

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063305497).
• BP6: Variant 18-31538880-T-C is Benign according to our data. Variant chr18-31538880-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44287.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=2, Uncertain_significance=1}. Variant chr18-31538880-T-C is described in Lovd as [Likely_benign]. Variant chr18-31538880-T-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5	c.1781T>C	p.Leu594Pro	missense_variant	12/15	ENST00000261590.13
DSG2	XM_047437315.1	c.1247T>C	p.Leu416Pro	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.1781T>C	p.Leu594Pro	missense_variant	12/15	1	NM_001943.5	P1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000630 AC: 157 AN: 249162 Hom.: 1 AF XY: 0.000636 AC XY: 86 AN XY: 135160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00964

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000352 AC: 514 AN: 1461874 Hom.: 2 Cov.: 32 AF XY: 0.000380 AC XY: 276 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000893

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74482

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000642 Hom.: 1

Bravo AF: 0.000408

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000472 AC: 4

ExAC AF: 0.000553 AC: 67

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2023	Variant summary: DSG2 c.1781T>C (p.Leu594Pro) results in a non-conservative amino acid change in 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 0.00063 in 249162 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 2.52 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00025), suggesting that the variant is benign. c.1781T>C has been reported in the literature in a heterozygous individual affected with Brugada syndrome (e.g. DiResta_2015) and in a case of sudden infant death syndrome reported as a VUS (e.g. Neubauer_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26220970, 21636032, 28074886). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as benign (n=3), likely benign (n=8), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2018	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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 27, 2014	Variant classified as Uncertain Significance - Favor Benign. The Leu594Pro varia nt in DSG2 has been identified in 4/8470 European American chromosomes by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs19968190 1). Our laboratory has previously detected this variant in 3 individuals (1 Asia n child with HCM and WPW, 1 Ashkenazi Jewish adult with possible DCM/ARVC, and 1 Ashkenazi Jewish adult with HCM). Leucine (Leu) at position 594 is not conserve d in mammals or evolutionarily distant species, raising the possibility that a c hange at this position may be tolerated. Additional computational prediction too ls suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clini cal significance of the Leu594Pro variant is uncertain, these data suggest that it is more likely to be benign. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DSG2: BP4 -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 20, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 14, 2018	- -

Arrhythmogenic right ventricular dysplasia 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 11, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Primary dilated cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 06, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

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	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.054
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.26
Sift	Benign	0.10	T
Sift4G	Benign	0.24	T
Polyphen		0.93	P
Vest4		0.49
MVP		0.64
MPC		0.43
ClinPred		0.074	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.77

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

Other links and lift over

dbSNP: rs199681901; hg19: chr18-29118843;