chr18-31546145-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001943.5(DSG2):​c.2759T>G​(p.Val920Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,614,176 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (β˜…β˜…).

Frequency

Genomes: 𝑓 0.0043 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0052 ( 26 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

3
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:20

Conservation

PhyloP100: 0.145
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-AS1 (HGNC:51311): (DSG2 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.004273176).
BP6
Variant 18-31546145-T-G is Benign according to our data. Variant chr18-31546145-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 44307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31546145-T-G is described in Lovd as [Pathogenic]. Variant chr18-31546145-T-G is described in Lovd as [Benign]. Variant chr18-31546145-T-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00429 (653/152286) while in subpopulation AMR AF= 0.0101 (155/15304). AF 95% confidence interval is 0.00883. There are 4 homozygotes in gnomad4. There are 313 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 653 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSG2NM_001943.5 linkc.2759T>G p.Val920Gly missense_variant Exon 15 of 15 ENST00000261590.13 NP_001934.2 Q14126
DSG2XM_047437315.1 linkc.2225T>G p.Val742Gly missense_variant Exon 16 of 16 XP_047293271.1
DSG2-AS1NR_045216.1 linkn.1346-239A>C intron_variant Intron 3 of 5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSG2ENST00000261590.13 linkc.2759T>G p.Val920Gly missense_variant Exon 15 of 15 1 NM_001943.5 ENSP00000261590.8 Q14126
DSG2-AS1ENST00000583706.5 linkn.1384-239A>C intron_variant Intron 3 of 5 5
DSG2-AS1ENST00000657343.1 linkn.697-239A>C intron_variant Intron 3 of 3

Frequencies

GnomAD3 genomes
AF:
0.00430
AC:
654
AN:
152168
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00196
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0101
Gnomad ASJ
AF:
0.0130
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00519
Gnomad OTH
AF:
0.00574
GnomAD3 exomes
AF:
0.00368
AC:
918
AN:
249158
Hom.:
5
AF XY:
0.00365
AC XY:
493
AN XY:
135176
show subpopulations
Gnomad AFR exome
AF:
0.00174
Gnomad AMR exome
AF:
0.00547
Gnomad ASJ exome
AF:
0.0124
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000294
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.00480
Gnomad OTH exome
AF:
0.00380
GnomAD4 exome
AF:
0.00524
AC:
7662
AN:
1461890
Hom.:
26
Cov.:
32
AF XY:
0.00503
AC XY:
3661
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00143
Gnomad4 AMR exome
AF:
0.00613
Gnomad4 ASJ exome
AF:
0.0139
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000290
Gnomad4 FIN exome
AF:
0.000262
Gnomad4 NFE exome
AF:
0.00597
Gnomad4 OTH exome
AF:
0.00490
GnomAD4 genome
AF:
0.00429
AC:
653
AN:
152286
Hom.:
4
Cov.:
32
AF XY:
0.00420
AC XY:
313
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.00195
Gnomad4 AMR
AF:
0.0101
Gnomad4 ASJ
AF:
0.0130
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00124
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00518
Gnomad4 OTH
AF:
0.00568
Alfa
AF:
0.00518
Hom.:
1
Bravo
AF:
0.00467
TwinsUK
AF:
0.00593
AC:
22
ALSPAC
AF:
0.00597
AC:
23
ESP6500AA
AF:
0.00154
AC:
6
ESP6500EA
AF:
0.00496
AC:
41
ExAC
AF:
0.00322
AC:
389
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00611
EpiControl
AF:
0.00640

ClinVar

Significance: Benign/Likely benign
Submissions summary: Uncertain:2Benign:20
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:7
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 24, 2015
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. We consider this variant to be of uncertain significance, likely benign, given it is present in multiple control samples and that it failed to segregate with disease in one family. This variant has been reported in 6 unrelated cases with either ARVC or DCM and as many as 6 total cases. Syrris et al (2006) initially identified the variant in a 17 yo male who had a sudden cardiac arrest, a left ventricular variant of ARVC was confirmed on autopsy. The proband’s father who had a positive phenotype on MRI and an abnormal signal average ECG was found to be genotype positive for the variant. Posch et al (2008) identified the variant in two families with dilated cardiomyopathy (note they refer to the variant as p.Val919Gly due to a numbering difference). However they report that the variant did not segregate with the phenotype in one family. In that family five affected relatives had the variant but one affected relative did not, indicating that it is likely not the primary causative variant of their disease. Christensen et al (2010) also reported the variant in 1 case that was clinically borderline for ARVC. Quarta et al (2011) found p.Val920Gly in 2 out of 100 families with ARVC. This is a conservative amino acid change with a nonpolar Valine replaced by a nonpolar Glyceine. SIFT predicts the amino acid change to be tolerated while PolyPhen predicts it to be probably damaging to the resulting protein. A variant in a nearby codon (p.Pro925Ser) has been reported in association with disease (University Medical Center Groningen ARVD/C Genetic Variants Database). Syrris et al (2006) reported that the variant was absent in 200 presumably healthy controls. Posch et al (2008) identified p.Val920Gly in 2 out of 432 presumably healthy control individuals. Christensen et al (2010) reported that the variant was present in 3 out of 650 individuals from a control population. Cox et al (2011) reported that the variant was absent in 200 controls. The variant is listed in dbSNP (rs142841727) with frequency data from the ClinSeq project, where it was seen in 8 of 660 individuals. It is listed in 1000Genomes, but only in reference to the dbSNP entry (as of April 17th, 2013). Additionally the variant was found in 41/4135 Caucasians and 6/1948 African American individuals in the NHLBI Exome Sequencing Project dataset (as of April 17th, 2013). -

Aug 21, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Val920Gly in exon 15 of DSG2: This variant has been reported in several indivi duals with ARVC or DCM but did not segregate with disease in one family member ( Syrris 2007, Posch 2008, Barahona-Dussault 2010, Christensen 2010). It has been identified in 0.5% (316/66608) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142841727). This freq uency strongly argues against a disease causing role but is too low to establish this with confidence. -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 08, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 23, 2017
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 04, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:4
Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

DSG2: BP4, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Aug 07, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1Benign:2
Jun 19, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

Cardiomyopathy Benign:2
Apr 08, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 03, 2020
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 10 Benign:2
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy;C0878544:Cardiomyopathy Benign:1
May 02, 2018
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Feb 08, 2017
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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
Sep 30, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as 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
0.095
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
15
DANN
Benign
0.90
DEOGEN2
Benign
0.21
T
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.46
T
MetaRNN
Benign
0.0043
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Uncertain
2.4
M
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-1.5
N
REVEL
Uncertain
0.52
Sift
Benign
0.040
D
Sift4G
Benign
0.23
T
Polyphen
0.67
P
Vest4
0.21
MVP
0.59
MPC
0.31
ClinPred
0.016
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.069
gMVP
0.26

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.

Other links and lift over

dbSNP: rs142841727; hg19: chr18-29126108; COSMIC: COSV55201278; COSMIC: COSV55201278; API