PLEKHG2

protein-coding

pleckstrin homology and RhoGEF domain containing G2, the group of Pleckstrin homology domain containing|Dbl family Rho GEFs

Gene summary

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]

MANE transcript

NM_022835.3

Inheritance

AR, AD

ClinVar variants

P:4U:367B:172

Top phenotype

Leukodystrophy and acquired microcephaly with or without dystonia

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr19:39,412,669-39,428,415

External References & Databases

Ensembl (ENSG00000090924)

Transcript & Mutation Effects

hg38 • Region Span ~15.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leukodystrophy and acquired microcephaly with or without dystonia;LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014766

Submitter: Illumina

epilepsyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: Ambry Genetics

leukodystrophy and acquired microcephaly with or without dystonia;MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014766

Submitter: PanelApp Australia

leukodystrophy and acquired microcephaly with or without dystonia;STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014766

Submitter: Labcorp Genetics (formerly Invitae)

leukodystrophy and acquired microcephaly with or without dystonia;LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014766

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Leukodystrophy and acquired microcephaly with or without dystoniaAR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26573021

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLEKHG2 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 396

not specifiedTotal: 252

Leukodystrophy and acquired microcephaly with or without dystonia;Total: 28

PLEKHG2-related disorderTotal: 23

Abnormality of neuronal migrationTotal: 2

Neurodevelopmental abnormalityTotal: 1

Abnormal brain morphologyTotal: 1

MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022835.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	126 clinvar	5 clinvar	136
missense	1 clinvar	1 clinvar	344 clinvar	31 clinvar	10 clinvar	387
nonsense		1 clinvar	6 clinvar			7
start loss						0
frameshift		1 clinvar	7 clinvar			8
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	1	3	367	157	15	543

Highest pathogenic variant AF is 0.00022259168

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022835.3	RefSeq	NP_073746.2	18	MANE Select
ENST00000425673.6	Ensembl	ENSP00000392906.2	18	MANE Select
NM_001351693.2	RefSeq	NP_001338622.1	19	Standard
NM_001351694.2	RefSeq	NP_001338623.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling by GPCR
Signal Transduction
Rho GTPase cycle
Signaling by Rho GTPases
NRAGE signals death through JNK

Biological Process

G protein-coupled receptor signaling pathway
regulation of actin filament polymerization
regulation of Rho protein signal transduction
positive regulation of apoptotic process
regulation of small GTPase mediated signal transduction

Molecular Function

guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409794
Coding exons: 18
Length: 15830
Individuals with no LoFs: 125680
Homozygous LoFs: 0
Heterozygous LoFs: 68
Defined: 125748
p: 0.000270

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.801	736	800	0.920	0.0000483	8744
Missense (PolyPhen)		243	267.22	0.90937		2844
Synonymous	0.894	311	332	0.938	0.0000202	3088
Loss of Function	3.94	25	57.2	0.437	0.00000340	599

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00057	0.00055	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00038	0.00038	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00030	0.00029	rare
South Asian	0.00027	0.00026	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be a transforming oncogene with exchange activity for CDC42 (By similarity). May be a guanine-nucleotide exchange factor (GEF) for RAC1 and CDC42. Activated by the binding to subunits beta and gamma of the heterotrimeric guanine nucleotide- binding protein (G protein) (PubMed:18045877). Involved in the regulation of actin polymerization (PubMed:26573021). {ECO:0000250|UniProtKB:Q6KAU7, ECO:0000269|PubMed:18045877, ECO:0000269|PubMed:26573021}.;
Disease: DISEASE: Leukodystrophy and acquired microcephaly with or without dystonia (LDAMD) [MIM:616763]: An autosomal recessive neurologic disorder characterized by profound mental retardation, dystonia, postnatal microcephaly, and white matter abnormalities consistent with leukodystrophy. {ECO:0000269|PubMed:26573021}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0979

Intolerance Scores

LoFtool: 0.407
RVIS EVS: 0.51
RVIS percentile EVS: 80.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.919

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium