chr18-31538787-T-G
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001943.5(DSG2):āc.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
Consequence
NM_001943.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSG2 | NM_001943.5 | c.1688T>G | p.Leu563Arg | missense_variant | 12/15 | ENST00000261590.13 | |
DSG2 | XM_047437315.1 | c.1154T>G | p.Leu385Arg | missense_variant | 13/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSG2 | ENST00000261590.13 | c.1688T>G | p.Leu563Arg | missense_variant | 12/15 | 1 | NM_001943.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000112 AC: 28AN: 249226Hom.: 0 AF XY: 0.000141 AC XY: 19AN XY: 135208
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727244
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74452
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 13, 2015 | Variant 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 submitter | clinical testing | GeneDx | Oct 27, 2016 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Jan 19, 2022 | This 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 submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 24, 2019 | - - |
Arrhythmogenic right ventricular dysplasia 10 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2023 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 06, 2017 | Variant 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 submitter | clinical testing | Ambry Genetics | Jan 23, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at