chr1-6468311-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_020631.6(PLEKHG5):c.2525G>A(p.Arg842Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,609,418 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R842W) has been classified as Uncertain significance.
Frequency
Consequence
NM_020631.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEKHG5 | NM_020631.6 | c.2525G>A | p.Arg842Gln | missense_variant | 20/21 | ENST00000377728.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEKHG5 | ENST00000377728.8 | c.2525G>A | p.Arg842Gln | missense_variant | 20/21 | 2 | NM_020631.6 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000270 AC: 41AN: 152078Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000191 AC: 45AN: 236140Hom.: 0 AF XY: 0.000186 AC XY: 24AN XY: 128838
GnomAD4 exome AF: 0.000425 AC: 620AN: 1457222Hom.: 0 Cov.: 32 AF XY: 0.000386 AC XY: 280AN XY: 724532
GnomAD4 genome ? AF: 0.000269 AC: 41AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74398
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 06, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 22, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2020 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 10, 2019 | The p.R842Q variant (also known as c.2525G>A), located in coding exon 19 of the PLEKHG5 gene, results from a G to A substitution at nucleotide position 2525. The arginine at codon 842 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 842 of the PLEKHG5 protein (p.Arg842Gln). This variant is present in population databases (rs149682441, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PLEKHG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 245769). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at