ARHGEF2

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

Basic information

Region (hg38): 1:155946851-156007070

Links

ENSG00000116584 ∙ NCBI:9181 ∙ OMIM:607560 ∙ HGNC:682 ∙ Uniprot:Q92974 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodevelopmental disorder with midbrain and hindbrain malformations (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodevelopmental disorder with midbrain and hindbrain malformations	AR	General	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	Craniofacial; Neurologic; Ophthalmologic	28453519

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ARHGEF2 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ARHGEF2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	14	4	19
missense			37	1	1	39
nonsense						0
start loss			1			1
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region				2		2
non coding				1	6	7
Total	0	0	39	16	11

Variants in ARHGEF2

This is a list of pathogenic ClinVar variants found in the ARHGEF2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-155947968-C-A		Microcephaly	Uncertain significance (-)
1-155947990-C-T			Benign (Dec 01, 2023)
1-155948014-G-T		not specified	Uncertain significance (Apr 13, 2023)
1-155948089-T-A		Neurodevelopmental disorder with midbrain and hindbrain malformations	Benign (Jul 14, 2021)
1-155950335-C-A			Benign (Dec 31, 2019)
1-155950412-C-T		not specified	Uncertain significance (Jan 29, 2024)
1-155950427-C-T		not specified	Uncertain significance (Nov 15, 2021)
1-155950464-G-A		not specified	Uncertain significance (Jan 17, 2024)
1-155950981-G-A		not specified	Uncertain significance (Aug 08, 2023)
1-155950988-C-G			Uncertain significance (Oct 01, 2022)
1-155951013-C-T		not specified	Uncertain significance (Feb 10, 2022)
1-155951060-T-C			Likely benign (Nov 01, 2023)
1-155951126-C-T		ARHGEF2-related disorder	Likely benign (Feb 22, 2019)
1-155951145-G-A		not specified	Uncertain significance (Jan 26, 2023)
1-155951252-G-T		not specified	Uncertain significance (May 17, 2023)
1-155951747-C-A		Neurodevelopmental disorder with midbrain and hindbrain malformations	Benign/Likely benign (Aug 13, 2021)
1-155952136-G-A		not specified	Uncertain significance (Sep 17, 2021)
1-155952148-C-A		Myoepithelial tumor	Uncertain significance (Nov 01, 2022)
1-155952182-G-A		not specified	Uncertain significance (May 23, 2023)
1-155952216-C-T		ARHGEF2-related disorder	Likely benign (Nov 14, 2019)
1-155952658-C-T		not specified	Uncertain significance (Aug 02, 2022)
1-155952663-C-T		not specified	Uncertain significance (Feb 14, 2023)
1-155952688-G-A		not specified	Uncertain significance (Feb 28, 2023)
1-155952711-G-A		not specified	Uncertain significance (Feb 10, 2022)
1-155952775-C-T		not specified	Uncertain significance (Aug 12, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ARHGEF2	protein_coding	protein_coding	ENST00000361247	22	60232

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	3.84e-7	125740	0	8	125748	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.61	378	633	0.597	0.0000425	6326
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.000139	0.000139
European (Non-Finnish)	0.0000353	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;Signal Transduction;TCR;Rho GTPase cycle;Signaling by Rho GTPases;Regulation of RAC1 activity;NRAGE signals death through JNK;Death Receptor Signalling;p75 NTR receptor-mediated signalling;G alpha (12/13) signalling events;GPCR downstream signalling;Reelin signaling pathway;Cell death signalling via NRAGE, NRIF and NADE;Regulation of RhoA activity (Consensus)

Recessive Scores

• pRec: 0.111

Intolerance Scores

• loftool: 0.191
• rvis_EVS: -0.93
• rvis_percentile_EVS: 9.61

Haploinsufficiency Scores

• pHI: 0.226
• hipred: Y
• hipred_score: 0.701
• ghis: 0.576

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.725

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Arhgef2
• Phenotype: growth/size/body region phenotype; cellular phenotype; hematopoietic system phenotype; immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Gene ontology

• Biological process: establishment of mitotic spindle orientation;cell morphogenesis;intracellular protein transport;actin filament organization;negative regulation of microtubule depolymerization;G protein-coupled receptor signaling pathway;positive regulation of interleukin-6 production;positive regulation of tumor necrosis factor production;regulation of Rho protein signal transduction;intracellular signal transduction;regulation of cell population proliferation;positive regulation of apoptotic process;innate immune response;positive regulation of neuron differentiation;positive regulation of transcription by RNA polymerase II;positive regulation of peptidyl-tyrosine phosphorylation;negative regulation of neurogenesis;regulation of small GTPase mediated signal transduction;positive regulation of NF-kappaB transcription factor activity;asymmetric neuroblast division;negative regulation of necroptotic process;cellular response to muramyl dipeptide;cellular response to tumor necrosis factor;cellular hyperosmotic response;negative regulation of podosome assembly;negative regulation of extrinsic apoptotic signaling pathway via death domain receptors;negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress;positive regulation of neuron migration
• Cellular component: podosome;cytoplasm;Golgi apparatus;spindle;cytosol;cytoskeleton;microtubule;bicellular tight junction;focal adhesion;cytoplasmic vesicle;vesicle;ruffle membrane;protein-containing complex;neuronal cell body;dendritic shaft;glutamatergic synapse;postsynaptic density, intracellular component
• Molecular function: guanyl-nucleotide exchange factor activity;Rho guanyl-nucleotide exchange factor activity;protein binding;microtubule binding;transcription factor binding;zinc ion binding;Rho GTPase binding;Rac guanyl-nucleotide exchange factor activity;Rac GTPase binding