ARHGEF2

protein-coding

Rho/Rac guanine nucleotide exchange factor 2, the group of Dbl family Rho GEFs|Pleckstrin homology domain containing|MicroRNA protein coding host genes

Gene summary

Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form complex with G proteins and stimulate rho-dependent signals. Alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Jun 2009]

MANE transcript

NM_001162383.2

Inheritance

ClinVar variants

P:2U:118B:25

Top phenotype

Neurodevelopmental disorder with midbrain and hindbrain malformations

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr1:155,946,851-156,007,070

External References & Databases

Ensembl (ENSG00000116584)

Transcript & Mutation Effects

hg38 • Region Span ~60.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with midbrain and hindbrain malformationsLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0056797

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with midbrain and hindbrain malformationsAR

Manifestation: Craniofacial; Neurologic; Ophthalmologic

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: 28453519

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARHGEF2 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 102

not providedTotal: 20

ARHGEF2-related disorderTotal: 12

Neurodevelopmental disorder with midbrain and hindbrain malformationsTotal: 9

MicrocephalyTotal: 2

Myoepithelial tumorTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001162383.2. 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	21 clinvar	1 clinvar	27
missense			102 clinvar	2 clinvar	1 clinvar	105
nonsense		1 clinvar	1 clinvar			2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)	1 clinvar		9 clinvar			10
Total	1	1	118	23	2	145

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001162383.2	RefSeq	NP_001155855.1	22	MANE Select
ENST00000361247.9	Ensembl	ENSP00000354837.4	22	MANE Select
NM_001162384.2	RefSeq	NP_001155856.1	22	Standard
NM_001350110.2	RefSeq	NP_001337039.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tight junction - Homo sapiens (human)
Fluid shear stress and atherosclerosis - Homo sapiens (human)
Pathogenic Escherichia coli infection - Homo sapiens (human)
Pathogenic Escherichia coli infection
Signaling by GPCR

Biological Process

establishment of mitotic spindle orientation
cell morphogenesis
intracellular protein transport
actin filament organization
negative regulation of microtubule depolymerization

Molecular Function

guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity
protein binding
microtubule binding
transcription factor binding

Cellular Component

podosome
cytoplasm
Golgi apparatus
spindle
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361247
Coding exons: 22
Length: 60232
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.61	378	633	0.597	0.0000425	6326
Missense (PolyPhen)		122	258.16	0.47257		2570
Synonymous	0.840	234	251	0.933	0.0000150	2064
Loss of Function	6.62	4	58.7	0.0682	0.00000391	552

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Activates Rho-GTPases by promoting the exchange of GDP for GTP. May be involved in epithelial barrier permeability, cell motility and polarization, dendritic spine morphology, antigen presentation, leukemic cell differentiation, cell cycle regulation, innate immune response, and cancer. Binds Rac-GTPases, but does not seem to promote nucleotide exchange activity toward Rac-GTPases, which was uniquely reported in PubMed:9857026. May stimulate instead the cortical activity of Rac. Inactive toward CDC42, TC10, or Ras-GTPases. Forms an intracellular sensing system along with NOD1 for the detection of microbial effectors during cell invasion by pathogens. Required for RHOA and RIP2 dependent NF-kappaB signaling pathways activation upon S.flexneri cell invasion. Involved not only in sensing peptidoglycan (PGN)-derived muropeptides through NOD1 that is independent of its GEF activity, but also in the activation of NF-kappaB by Shigella effector proteins (IpgB2 and OspB) which requires its GEF activity and the activation of RhoA. Involved in innate immune signaling transduction pathway promoting cytokine IL6/interleukin-6 and TNF- alpha secretion in macrophage upon stimulation by bacterial peptidoglycans; acts as a signaling intermediate between NOD2 receptor and RIPK2 kinase. Contributes to the tyrosine phosphorylation of RIPK2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Overexpression activates Rho-, but not Rac-GTPases, and increases paracellular permeability (By similarity). Involved in neuronal progenitor cell division and differentiation (PubMed:28453519). Involved in the migration of precerebellar neurons (By similarity). {ECO:0000250|UniProtKB:Q60875, ECO:0000250|UniProtKB:Q865S3, ECO:0000269|PubMed:19043560, ECO:0000269|PubMed:21887730, ECO:0000269|PubMed:28453519, ECO:0000269|PubMed:9857026}.;
Disease: DISEASE: Neurodevelopmental disorder with midbrain and hindbrain malformations (NEDMHM) [MIM:617523]: An autosomal recessive neurodevelopmental disorder characterized by intellectual disability, speech delay, mild microcephaly, midbrain-hindbrain malformations, and variable dysmorphic features. {ECO:0000269|PubMed:28453519}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.111

Intolerance Scores

LoFtool: 0.191
RVIS EVS: -0.93
RVIS percentile EVS: 9.61

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.725

Gene Damage Prediction

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