dbSNP rs201201843: PLEKHG2:p.Arg204Trp (chr19-39416866-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PS3PP5BP4BS2_Supporting

The NM_022835.3(PLEKHG2):c.610C>T(p.Arg204Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,608,326 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002556727: Functional studies demonstrate decreased basal and stimulated RhoGEF activity of the R204 mutant compared with wildtype in luciferase assays, suggesting the R204 variant impairs the ability of the PLEKHG2 catalytic domain to form an active conformation (PMID:26573021) (PS3_moderate)." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

PLEKHG2
NM_022835.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 3.45

Publications

7 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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
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 3 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002556727: Functional studies demonstrate decreased basal and stimulated RhoGEF activity of the R204 mutant compared with wildtype in luciferase assays, suggesting the R204 variant impairs the ability of the PLEKHG2 catalytic domain to form an active conformation (PMID:26573021) (PS3_moderate).; SCV004021197: Experimental evidence evaluating an impact on protein function suggests this variant can impair normal protein function (example: Edvardson_2016). PMID: 26573021; SCV005415919: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV002261936: Experimental studies have shown that this missense change affects PLEKHG2 function (PMID: 26573021).

PP5

Variant 19-39416866-C-T is Pathogenic according to our data. Variant chr19-39416866-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522394.

BP4

Computational evidence support a benign effect (MetaRNN=0.35702795). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022835.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHG2	NM_022835.3	MANE Select	c.610C>T	p.Arg204Trp	missense	Exon 7 of 19	NP_073746.2	Q9H7P9-1
PLEKHG2	NM_001351693.2		c.433C>T	p.Arg145Trp	missense	Exon 7 of 20	NP_001338622.1	E7ESZ3
PLEKHG2	NM_001351694.2		c.610C>T	p.Arg204Trp	missense	Exon 7 of 18	NP_001338623.1	Q9H7P9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLEKHG2	ENST00000425673.6	TSL:2 MANE Select	c.610C>T	p.Arg204Trp	missense	Exon 7 of 19	ENSP00000392906.2	Q9H7P9-1
PLEKHG2	ENST00000205135.8	TSL:1	c.298C>T	p.Arg100Trp	missense	Exon 5 of 15	ENSP00000205135.3	H7BXC7
PLEKHG2	ENST00000942561.1		c.610C>T	p.Arg204Trp	missense	Exon 6 of 18	ENSP00000612620.1

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000356

AC:

AN:

241264

AF XY:

0.000326

show subpopulations

Gnomad AFR exome

AF:

0.0000668

Gnomad AMR exome

AF:

0.000178

Gnomad ASJ exome

AF:

0.000724

Gnomad EAS exome

AF:

0.00140

Gnomad FIN exome

AF:

0.00160

Gnomad NFE exome

AF:

0.0000921

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.000206

AC:

300

AN:

1455996

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

149

AN XY:

724234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33340

American (AMR)

AF:

0.000137

AC:

AN:

43954

Ashkenazi Jewish (ASJ)

AF:

0.000736

AC:

AN:

25830

East Asian (EAS)

AF:

0.00224

AC:

AN:

39646

South Asian (SAS)

AF:

0.0000817

AC:

AN:

85696

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

51940

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000676

AC:

AN:

1109670

Other (OTH)

AF:

0.000482

AC:

AN:

60176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000381

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41574

American (AMR)

AF:

0.000784

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68012

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

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:

0.000248

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000190

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leukodystrophy and acquired microcephaly with or without dystonia; (5)

not provided (2)

PLEKHG2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.36

MetaSVM

Uncertain

0.064

MutationAssessor

Uncertain

2.8

PhyloP100

3.5

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.70

MVP

0.82

ClinPred

0.094

GERP RS

4.9

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.82

gMVP

0.66

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over