chr1-6467972-T-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_020631.6(PLEKHG5):​c.2864A>G​(p.Lys955Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000429 in 1,561,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

PLEKHG5
NM_020631.6 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: -0.0940

Publications

0 publications found
Variant links:
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]
PLEKHG5 Gene-Disease associations (from GenCC):
  • neuromuscular disease
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • Charcot-Marie-Tooth disease recessive intermediate C
    Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • neuronopathy, distal hereditary motor, autosomal recessive 4
    Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.004238695).
BP6
Variant 1-6467972-T-C is Benign according to our data. Variant chr1-6467972-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 572080.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS1
Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000426 (60/1409148) while in subpopulation AMR AF = 0.00138 (51/36974). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAdExome4. There are 34 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLEKHG5NM_020631.6 linkc.2864A>G p.Lys955Arg missense_variant Exon 20 of 21 ENST00000377728.8 NP_065682.2 O94827-5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLEKHG5ENST00000377728.8 linkc.2864A>G p.Lys955Arg missense_variant Exon 20 of 21 2 NM_020631.6 ENSP00000366957.3 O94827-5

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
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
GnomAD2 exomes
AF:
0.000319
AC:
54
AN:
169046
AF XY:
0.000308
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00147
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00347
GnomAD4 exome
AF:
0.0000426
AC:
60
AN:
1409148
Hom.:
0
Cov.:
32
AF XY:
0.0000488
AC XY:
34
AN XY:
696732
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32092
American (AMR)
AF:
0.00138
AC:
51
AN:
36974
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25300
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36456
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80918
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
46800
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5284
European-Non Finnish (NFE)
AF:
9.20e-7
AC:
1
AN:
1086904
Other (OTH)
AF:
0.000137
AC:
8
AN:
58420
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.511
Heterozygous variant carriers
0
6
11
17
22
28
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152230
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74370
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41466
American (AMR)
AF:
0.000458
AC:
7
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10632
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.554
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000726
Hom.:
0
Bravo
AF:
0.000283
ExAC
AF:
0.000300
AC:
35

ClinVar

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

Submissions by phenotype

Neuronopathy, distal hereditary motor, autosomal recessive 4;C3809309:Charcot-Marie-Tooth disease recessive intermediate C Uncertain:1
Dec 30, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 955 of the PLEKHG5 protein (p.Lys955Arg). This variant is present in population databases (rs771066341, gnomAD 0.1%). 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: 572080). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine 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. -

Inborn genetic diseases Benign:1
Jun 12, 2025
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.057
BayesDel_addAF
Benign
-0.60
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
0.34
DANN
Benign
0.62
DEOGEN2
Benign
0.097
.;.;.;.;.;.;.;T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.014
N
LIST_S2
Benign
0.59
T;.;T;T;T;.;T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.0042
T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.83
.;.;.;.;.;.;.;N
PhyloP100
-0.094
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.48
N;N;N;N;N;N;N;N
REVEL
Benign
0.022
Sift
Benign
0.93
T;T;T;T;T;T;T;T
Sift4G
Benign
0.52
T;T;T;T;T;T;T;T
Polyphen
0.0
.;.;.;.;B;.;.;B
Vest4
0.030
MutPred
0.21
.;.;.;.;.;.;.;Loss of ubiquitination at K1011 (P = 0.0037);
MVP
0.12
MPC
0.21
ClinPred
0.013
T
GERP RS
0.88
Varity_R
0.019
gMVP
0.23
Mutation Taster
=96/4
polymorphism

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

Other links and lift over

dbSNP: rs771066341; hg19: chr1-6528032; API