rs370673772

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

The NM_022835.3(PLEKHG2):c.1708G>A(p.Gly570Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,522,852 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 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

PLEKHG2
NM_022835.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 0.264

Publications

2 publications found

Variant links:

Genes affected

PLEKHG2 (HGNC:29515): (pleckstrin homology and RhoGEF domain containing G2) The protein encoded by this gene is a RhoGTPase that can activate CDC42 by promoting exchange of GDP for GTP on CDC42. The encoded protein is activated by binding to the beta and gamma subunits of heterotrimeric guanine nucleotide-binding protein. Defects in this gene have been associated with leukodystrophy and acquired microcephaly with or without dystonia. [provided by RefSeq, May 2017]

PLEKHG2 Gene-Disease associations (from GenCC):

leukodystrophy and acquired microcephaly with or without dystonia;
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

PLEKHG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant 19-39422762-G-A is Pathogenic according to our data. Variant chr19-39422762-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402163.

BP4

Computational evidence support a benign effect (MetaRNN=0.039737165). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHG2	NM_022835.3 link	c.1708G>A	p.Gly570Arg	missense_variant	Exon 18 of 19	ENST00000425673.6	NP_073746.2	Q9H7P9-1
PLEKHG2	NM_001351693.2 link	c.1531G>A	p.Gly511Arg	missense_variant	Exon 18 of 20		NP_001338622.1
PLEKHG2	NM_001351694.2 link	c.1677+474G>A		intron_variant	Intron 17 of 17		NP_001338623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHG2	ENST00000425673.6 link	c.1708G>A	p.Gly570Arg	missense_variant	Exon 18 of 19	2	NM_022835.3	ENSP00000392906.2		Q9H7P9-1

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000112

AC:

AN:

178710

AF XY:

0.000139

show subpopulations

Gnomad AFR exome

AF:

0.0000649

Gnomad AMR exome

AF:

0.000141

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000126

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000759

AC:

104

AN:

1370830

Hom.:

Cov.:

AF XY:

0.0000818

AC XY:

AN XY:

672624

show subpopulations

African (AFR)

AF:

0.000165

AC:

AN:

30272

American (AMR)

AF:

0.000102

AC:

AN:

29478

Ashkenazi Jewish (ASJ)

AF:

0.000100

AC:

AN:

19990

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39040

South Asian (SAS)

AF:

0.000185

AC:

AN:

70390

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49910

Middle Eastern (MID)

AF:

0.000188

AC:

AN:

5316

European-Non Finnish (NFE)

AF:

0.0000682

AC:

AN:

1070062

Other (OTH)

AF:

0.000106

AC:

AN:

56372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000987

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000375

Hom.:

Bravo

AF:

0.000159

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000111

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 570 of the PLEKHG2 protein (p.Gly570Arg). This variant is present in population databases (rs370673772, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of leukodystrophy and acquired microcephaly with or without dystonia (PMID: 26539891). ClinVar contains an entry for this variant (Variation ID: 402163). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". 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. -

Jun 20, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Abnormal brain morphology

Pathogenic:1

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.0020

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.040

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.48

N;.

PhyloP100

0.26

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.75

.;N

REVEL

Benign

0.092

Sift

Benign

0.40

.;T

Sift4G

Benign

0.23

T;T

Polyphen

0.12

B;B

Vest4

0.21

MutPred

0.12

Gain of glycosylation at K567 (P = 0.0678);.;

MVP

0.21

ClinPred

0.0086

GERP RS

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.023

gMVP

0.12

Mutation Taster

=97/3

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over