ARFGEF2

ADP ribosylation factor guanine nucleotide exchange factor 2, the group of Armadillo like helical domain containing|ARFGEF family|A-kinase anchoring proteins

Basic information

Region (hg38): 20:48921711-49036693

Links

ENSG00000124198

∙ NCBI:10564 ∙ OMIM:605371 ∙ HGNC:15853 ∙ Uniprot:Q9Y6D5 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

periventricular heterotopia with microcephaly, autosomal recessive (Strong), mode of inheritance: AR
periventricular heterotopia with microcephaly, autosomal recessive (Strong), mode of inheritance: AR
periventricular nodular heterotopia (Supportive), mode of inheritance: AD
periventricular heterotopia with microcephaly, autosomal recessive (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Heterotopia, periventricular, autosomal recessive	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	Neurologic	12682315; 14647276; 23755938
In addition to neurologic manifestations, cardiomyoptathy and frequent infections have been described, but this finding may be coincidental; Recurrent infections have been described in several individuals, but it is unclear if this is a primary manifestation or secondary to neurodegenerative sequelae

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ARFGEF2 gene.

not_provided (439 variants)
Inborn_genetic_diseases (153 variants)
Periventricular_heterotopia_with_microcephaly,_autosomal_recessive (109 variants)
not_specified (100 variants)
ARFGEF2-related_disorder (40 variants)
Intellectual_disability (4 variants)
Periventricular_laminar_heterotopia (3 variants)
EBV-positive_nodal_T-_and_NK-cell_lymphoma (1 variants)
Hydrocephalus (1 variants)
Seizure (1 variants)
Global_developmental_delay (1 variants)
Microcephaly (1 variants)
See_cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ARFGEF2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000006420.3. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			13 clinvar	142 clinvar	3 clinvar	158
missense	1 clinvar		309 clinvar	13 clinvar	1 clinvar	324
nonsense	6 clinvar	4 clinvar	1 clinvar			11
start loss						0
frameshift	6 clinvar	2 clinvar	1 clinvar			9
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar				4
Total	15	8	324	155	4

Highest pathogenic variant AF is 0.000006572461

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ARFGEF2	protein_coding	protein_coding	ENST00000371917	39	114804

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000743	125722	0	26	125748	0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.60	731	957	0.764	0.0000560	11827
Missense in Polyphen		92	207.44	0.44351		2537
Synonymous	0.822	340	360	0.945	0.0000222	3335
Loss of Function	7.65	16	97.5	0.164	0.00000557	1127

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000435	0.000427
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000880	0.0000791
Middle Eastern	0.000109	0.000109
South Asian	0.000163	0.000163
Other	0.00	0.00

dbNSFP

Source: dbNSFP

Function: FUNCTION: Promotes guanine-nucleotide exchange on ARF1 and ARF3 and to a lower extent on ARF5 and ARF6. Promotes the activation of ARF1/ARF5/ARF6 through replacement of GDP with GTP. Involved in the regulation of Golgi vesicular transport. Required for the integrity of the endosomal compartment. Involved in trafficking from the trans-Golgi network (TGN) to endosomes and is required for membrane association of the AP-1 complex and GGA1. Seems to be involved in recycling of the transferrin receptor from recycling endosomes to the plasma membrane. Probably is involved in the exit of GABA(A) receptors from the endoplasmic reticulum. Involved in constitutive release of tumor necrosis factor receptor 1 via exosome-like vesicles; the function seems to involve PKA and specifically PRKAR2B. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways. {ECO:0000269|PubMed:12051703, ECO:0000269|PubMed:12571360, ECO:0000269|PubMed:15385626, ECO:0000269|PubMed:16477018, ECO:0000269|PubMed:17276987, ECO:0000269|PubMed:18625701, ECO:0000269|PubMed:20360857}.;
Disease: DISEASE: Periventricular nodular heterotopia 2 (PVNH2) [MIM:608097]: A developmental disorder characterized by the presence of periventricular nodules of cerebral gray matter, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. PVNH2 is an autosomal recessive form characterized by microcephaly (small brain), severe developmental delay and recurrent infections. No anomalies extrinsic to the central nervous system, such as dysmorphic features or grossly abnormal endocrine or other conditions, are associated with PVNH2. {ECO:0000269|PubMed:14647276, ECO:0000269|PubMed:23812912, ECO:0000269|PubMed:25160555}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Endocytosis - Homo sapiens (human);thrombin signaling and protease-activated receptors;Metabolism of proteins;Chaperonin-mediated protein folding;Association of TriC/CCT with target proteins during biosynthesis;adp-ribosylation factor;Protein folding (Consensus)

Recessive Scores

pRec: 0.150

Intolerance Scores

loftool: 0.395
rvis_EVS: -2.39
rvis_percentile_EVS: 1.1

Haploinsufficiency Scores

pHI: 0.605
hipred: Y
hipred_score: 0.756
ghis: 0.650

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.951

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Arfgef2
Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); 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); growth/size/body region phenotype; cellular phenotype;

Gene ontology

Biological process: receptor recycling;exocytosis;Golgi to plasma membrane transport;endosome organization;endomembrane system organization;protein transport;vesicle-mediated transport;regulation of ARF protein signal transduction;positive regulation of tumor necrosis factor production;intracellular signal transduction
Cellular component: Golgi membrane;trans-Golgi network;microtubule organizing center;cytosol;axonemal microtubule;membrane;cell junction;cytoplasmic vesicle;asymmetric synapse;symmetric synapse;dendritic spine;perinuclear region of cytoplasm;recycling endosome
Molecular function: guanyl-nucleotide exchange factor activity;ARF guanyl-nucleotide exchange factor activity;protein binding;myosin binding;protein kinase A regulatory subunit binding;GABA receptor binding