18-31538787-T-G

Variant summary

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

The NM_001943.5(DSG2):ā€‹c.1688T>Gā€‹(p.Leu563Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,614,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. L563P) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 32)
Exomes š‘“: 0.000029 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.998
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]

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=0.012969822).
BP6
Variant 18-31538787-T-G is Benign according to our data. Variant chr18-31538787-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228630.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}.
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DSG2NM_001943.5 linkuse as main transcriptc.1688T>G p.Leu563Arg missense_variant 12/15 ENST00000261590.13
DSG2XM_047437315.1 linkuse as main transcriptc.1154T>G p.Leu385Arg missense_variant 13/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DSG2ENST00000261590.13 linkuse as main transcriptc.1688T>G p.Leu563Arg missense_variant 12/151 NM_001943.5 P1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00115
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000112
AC:
28
AN:
249226
Hom.:
0
AF XY:
0.000141
AC XY:
19
AN XY:
135208
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00156
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:
42
AN:
1461884
Hom.:
0
Cov.:
32
AF XY:
0.0000289
AC XY:
21
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00103
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152272
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000680
Hom.:
0
Bravo
AF:
0.0000907
ExAC
AF:
0.0000745
AC:
9
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 13, 2015Variant classified as Uncertain Significance - Favor Benign. The p.Leu563Arg var iant in DSG2 has not been previously reported in individuals with cardiomyopathy , but has been identified in 0.1% (9/8594) East Asian chromosomes by the Exome A ggregation Consortium Sequencing Project (http://exac.broadinstitute.org). Leuci ne (Leu) at position 563 is not conserved in mammals or evolutionarily distant s pecies and the mouse carries arginine (Arg) at this position, raising the possib ility that this change may be tolerated. In summary, while the clinical signific ance of the p.Leu563Arg variant is uncertain, its frequency and the presence of the variant amino acid in another mammal suggests that it is more likely to be b enign. -
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 27, 2016This 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. -
Likely benign, criteria provided, single submitterclinical testingPhosphorus, Inc.Jan 19, 2022This missense variant results in an amino acid substitution of Leucine with Arginine at codon 563 of the DSG2 gene (transcript: NM_001943.3). This variant has an entry in ClinVar (228630) NM_001943.5(DSG2):c.1688T>G (p.Leu563Arg). This variant occurred in gnomAD with a total MAF of 0.0110% and with the highest MAF of 0.1566% in the East Asian population. This position is not conserved. In silico functional algorithms predict this variant to be benign (PolyPhen) and tolerated (SIFT). However, no functional studies were performed to confirm either of those predictions. The variant has not occurred in the literature in association with the disease. Considering that the variant has a relatively high frequency in the subpopulation, it has been classified as Likely Benign. -
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 24, 2019- -
Arrhythmogenic right ventricular dysplasia 10 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 22, 2023- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 06, 2017Variant summary: The DSG2 c.1688T>G (p.Leu563Arg) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 9/120636 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.001047 (9/8594). This frequency is about 105 times the estimated maximal expected allele frequency of a pathogenic DSG2 variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant has been reported in a Japanese individual with West syndrome without evidence for causality (Hino-Fukuyo_2015). Another clinical diagnostic laboratory classified this variant as uncertain significance, without evidence for independent evaluation. Taken together, this variant is classified as likely benign. -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2023This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
11
DANN
Benign
0.67
DEOGEN2
Benign
0.12
T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.53
T
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.013
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.89
N
REVEL
Benign
0.024
Sift
Benign
0.36
T
Sift4G
Benign
0.53
T
Polyphen
0.0060
B
Vest4
0.21
MutPred
0.36
Gain of disorder (P = 0.0312);
MVP
0.59
MPC
0.11
ClinPred
0.0070
T
GERP RS
-0.66
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.070
gMVP
0.63

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: rs780469370; hg19: chr18-29118750; API