rs202191898
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_020631.6(PLEKHG5):c.2458G>C(p.Gly820Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000162 in 1,609,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G820S) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
PLEKHG5
NM_020631.6 missense
NM_020631.6 missense
Scores
6
10
1
Clinical Significance
Conservation
PhyloP100: 6.69
Genes affected
PLEKHG5 (HGNC:29105): (pleckstrin homology and RhoGEF domain containing G5) This gene encodes a protein that activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in this gene are associated with autosomal recessive distal spinal muscular atrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEKHG5 | NM_020631.6 | c.2458G>C | p.Gly820Arg | missense_variant | 20/21 | ENST00000377728.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEKHG5 | ENST00000377728.8 | c.2458G>C | p.Gly820Arg | missense_variant | 20/21 | 2 | NM_020631.6 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000293 AC: 7AN: 238782Hom.: 0 AF XY: 0.0000231 AC XY: 3AN XY: 130082
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GnomAD4 exome AF: 0.0000165 AC: 24AN: 1457448Hom.: 0 Cov.: 32 AF XY: 0.0000166 AC XY: 12AN XY: 724766
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152302Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74466
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease recessive intermediate C Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 12, 2013 | - - |
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 | Jan 11, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 820 of the PLEKHG5 protein (p.Gly820Arg). This variant is present in population databases (rs202191898, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 23844677). ClinVar contains an entry for this variant (Variation ID: 60779). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects PLEKHG5 function (PMID: 23844677). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;D;D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;D;D;.;.;D
Vest4
MutPred
0.29
.;.;.;.;.;.;.;.;Gain of methylation at G876 (P = 0.0346);
MVP
MPC
1.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at