18-31498295-T-A
Position:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The ENST00000261590.13(DSG2):c.44T>A(p.Leu15Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000931 in 1,263,690 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L15L) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00098 ( 0 hom. )
Consequence
DSG2
ENST00000261590.13 missense, splice_region
ENST00000261590.13 missense, splice_region
Scores
1
1
17
Splicing: ADA: 0.001275
2
Clinical Significance
Conservation
PhyloP100: 1.71
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]
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=0.036025077).
BP6
Variant 18-31498295-T-A is Benign according to our data. Variant chr18-31498295-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44318.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=7}. Variant chr18-31498295-T-A is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 82 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DSG2 | NM_001943.5 | c.44T>A | p.Leu15Gln | missense_variant, splice_region_variant | 1/15 | ENST00000261590.13 | NP_001934.2 | |
| DSG2 | XM_047437315.1 | c.-529T>A | splice_region_variant, 5_prime_UTR_variant | 1/16 | XP_047293271.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DSG2 | ENST00000261590.13 | c.44T>A | p.Leu15Gln | missense_variant, splice_region_variant | 1/15 | 1 | NM_001943.5 | ENSP00000261590 | P1 | |
| DSG2 | ENST00000683654.1 | c.44T>A | p.Leu15Gln | missense_variant, splice_region_variant | 1/7 | ENSP00000506971 | ||||
| DSG2 | ENST00000682241.2 | c.44T>A | p.Leu15Gln | missense_variant, splice_region_variant | 1/7 | ENSP00000507600 | ||||
| DSG2 | ENST00000585206.1 | c.44T>A | p.Leu15Gln | missense_variant, splice_region_variant | 1/6 | 2 | ENSP00000462503 |
Frequencies
GnomAD3 genomes 0.000540 AC: 82AN: 151886Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
82
AN:
151886
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000236 AC: 6AN: 25416Hom.: 0 AF XY: 0.000303 AC XY: 4AN XY: 13216
GnomAD3 exomes
AF:
AC:
6
AN:
25416
Hom.:
AF XY:
AC XY:
4
AN XY:
13216
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000985 AC: 1095AN: 1111686Hom.: 0 Cov.: 30 AF XY: 0.000990 AC XY: 523AN XY: 528156
GnomAD4 exome
AF:
AC:
1095
AN:
1111686
Hom.:
Cov.:
30
AF XY:
AC XY:
523
AN XY:
528156
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000539 AC: 82AN: 152004Hom.: 0 Cov.: 32 AF XY: 0.000592 AC XY: 44AN XY: 74308
GnomAD4 genome
AF:
AC:
82
AN:
152004
Hom.:
Cov.:
32
AF XY:
AC XY:
44
AN XY:
74308
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
1
ALSPAC
AF:
AC:
1
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
18
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:5
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 09, 2021 | This variant is associated with the following publications: (PMID: 20031616, 18639457, 28600387, 31402444) - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jun 14, 2017 | Given the weak case data, the number of cases with other pathogenic variants, gene constraint data and its presence in population databases, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant may alter RNA splicing. The variant has been seen in at least 33 unrelated cases of cardiomyopathy (not including this patient's family). There is weak case data. Some of these patients had additional pathogenic variants identified. This variant is present in ClinVar, classified as a variant of uncertain significance by 5 labs. It has been seen in at least 6 patients from 5 families. The Laboratory for Molecular Medicine has seen this variant in 5 individuals from 5 different families and they report the following cases: 1 child with HCM, 1 child with DCM who carried a disease-causing variant in another gene, and 2 adults with DCM. This variant is reported once in the literature: in a 55 year old male with "probable" ARVC. The diagnosis was based on the presence of epsilon eaves and left bundle branch ventricular tachycardia. Variant classification was based on physciocemical properties of the amino acids involved, the evolutionary conservation of the amino acid, and localization within a functionally important domain (Bhuiyan et al, 2009). There is weak evidence linking missense variants in DSG2 with DCM: Of note, Kapplinger et al. (2011) from Michael Ackerman’s group have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants—similar to the 21% yield in 175 Dutch and U.S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC-related genes need to be interpreted with caution. Kapplinger et al. also report a “hot spot†for DSG2 variants between amino acids 24-388 in patients with ARVC but not in controls. Furthermore, per the ExAC database's constraint data, DSG2 is tolerant of both missense (Z= -1.20) and loss of function variation (pLI=0.00). This constraint data is supported in a paper by Walsh and colleagues in 2016: in comparing the genetic variation between cases and controls, neither missense variants nor truncating variants in DSG2 were significantly enriched in cases versus controls. According to this data, missense variants in DSG2 are unlikely to significantly increase an individual's risk to develop DCM. Per the genetic testing report, "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." The leucine at codon 15 is moderately conserved across species, as are neighboring amino acids. Other variants reported in ClinVar at this codon and close by are called variants of uncertain significance, or likely benign. The variant was reported online in 18 of 28,029 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 12 of 12,221 individuals of European descent (MAF=0.07%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that this is a low-quality site, with depth of coverage less than 20x. - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not specified Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 10, 2019 | The p.Leu15Gln variant (rs372174546) has been previously reported as an unclassified variant in one patient with probable arrhythmogenic right ventricular dysplasia / cardiomyopathy (Bhuiyan 2009), one from a cohort of cardiac arrest survivors (Mellor 2017), and has been reported to ClinVar (Variation ID: 44318). This variant is listed in the genome Aggregation Database with an overall population frequency of 0.02 percent (identified on 18 out of 56,058 chromosomes). The leucine at position 15 is weakly conserved (Alamut v2.8.1) and computational analyses of the effects of the p.Leu15Gln variant on protein structure and function indicate a neutral effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Leu15Gln variant with certainty. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 28, 2015 | Variant classified as Uncertain Significance - Favor Benign. The p.Leu15Gln vari ant in DSG2 has been reported in 1 Caucasian adult with "probable" ARVC (Bhuiyan 2009), and has been identified by our laboratory in 4 individuals: 1 child with HCM, 1 child with DCM who carried a disease-causing variant in another gene, an d 2 adults with DCM. This variant has also been identified in 0.4% (6/1706) of E uropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs372174546). This variant is located in the last three bas es of the exon, which is part of the 5? splice region. Although computational to ols do not suggest an impact to the functionality of the 5' splice site, this in formation is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Leu15Gln variant is uncertain, its frequency suggests that it is more likely to be benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 20, 2021 | Variant summary: DSG2 c.44T>A (p.Leu15Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant also alters a conserved nucleotide in the exonic-splice region located at the second to last nucleotide of exon 1 before the canonical intron 1 splice donor site. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00032 in 56632 control chromosomes. The observed variant frequency is approximately 13 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 benign. c.44T>A has been reported in the literature in individuals affected with ARVD (Bhuyian_2009), ARVC (Mellor_2017, Ye_2019). These report(s) do not provide unequivocal conclusions about association of the variant with DSG2 associated Cardiomyopathy/ARVD/ARVC. One recent report proposes a categorization of this variant as a disease-modifier while acknowledging its prevalence greater than expected for a monogenic disease causation (Ye_2019). However, this is not supported by convincing data supporting its role as a disease modifier. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=8, likely benign, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. One submitter reports an unspecified co-occurence with a mutation in another gene that clearly explains a proband's phenotype. Based on the evidence outlined above, the variant was classified as likely benign. - |
Arrhythmogenic right ventricular dysplasia 10 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 28, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 27, 2022 | This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 15 of the DSG2 protein (p.Leu15Gln). This variant is present in population databases (rs372174546, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with DSG2-related conditions (PMID: 20031616, 31402444). ClinVar contains an entry for this variant (Variation ID: 44318). 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. 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 Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 02, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 08, 2022 | - - |
Primary familial dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Nov 30, 2016 | - - |
Dilated cardiomyopathy 1BB Uncertain:1
| Uncertain significance, 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 VUS-3C. 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 10; 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 leucine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of ARVD 10 or DCM. (SB) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated signal sequence domain (PMID: 30885746). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in a few ARVC related studies without proper classification (PMID: 20031616, 28600387, 30885746, 31402444). It has also been reported as VUS in individuals with ARVC and likely benign in individuals with cardiovascular phenotypes in ClinVar and various other databases (LOVD, ARVC genetic variant db). (I) 0905 - No published segregation evidence has been identified for this variant. (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 - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 04, 2019 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
MutationTaster
Benign
N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Benign
Sift
Benign
T;.
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at