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): 20:48921710-49036693

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 (450 variants)
• Periventricular heterotopia with microcephaly, autosomal recessive (161 variants)
• not specified (104 variants)
• Inborn genetic diseases (47 variants)
• Periventricular laminar heterotopia (6 variants)
• Intellectual disability (3 variants)
• - (2 variants)
• Global developmental delay (1 variants)
• Global developmental delay;Seizure;Hydrocephalus (1 variants)
• ARFGEF2-related condition (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.

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			13	88	3	104
missense			210	1		211
nonsense	4	3				7
start loss						0
frameshift	5	2				7
inframe indel			2			2
splice donor/acceptor (+/-2bp)	1	1				2
splice region			16	16		32
non coding			61	90	75	226
Total	10	6	286	179	78

Highest pathogenic variant AF is 0.00000657

Variants in ARFGEF2

This is a list of pathogenic ClinVar variants found in the ARFGEF2 region.

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

Position	Type	Phenotype	Significance	ClinVar
20-48921796-C-T		Periventricular heterotopia with microcephaly, autosomal recessive	Benign (Jun 14, 2018)
20-48921822-C-A		Periventricular heterotopia with microcephaly, autosomal recessive	Uncertain significance (Jan 13, 2018)
20-48921830-C-T		Periventricular heterotopia with microcephaly, autosomal recessive	Uncertain significance (Jan 13, 2018)
20-48921847-G-A		Periventricular heterotopia with microcephaly, autosomal recessive • ARFGEF2-related disorder	Conflicting classifications of pathogenicity (Jul 15, 2022)
20-48921851-C-T		Periventricular heterotopia with microcephaly, autosomal recessive	Conflicting classifications of pathogenicity (Mar 15, 2021)
20-48921858-GCGGGGCCGTCAGCCCCCGCCGGGC-G		not specified • ARFGEF2-related disorder	Likely benign (Jul 29, 2019)
20-48921863-G-A		not specified	Likely benign (Nov 19, 2015)
20-48921865-C-T			Likely benign (Apr 30, 2018)
20-48921885-G-A		Periventricular heterotopia with microcephaly, autosomal recessive	Uncertain significance (Jan 12, 2018)
20-48921928-G-A			Likely benign (Jan 13, 2024)
20-48921937-G-A		not specified	Conflicting classifications of pathogenicity (Jun 13, 2022)
20-48921940-G-A			Likely benign (Feb 16, 2023)
20-48921968-C-T			Uncertain significance (Mar 13, 2014)
20-48921970-C-G		ARFGEF2-related disorder	Benign/Likely benign (Oct 17, 2023)
20-48921980-C-T		Periventricular heterotopia with microcephaly, autosomal recessive	Likely pathogenic (-)
20-48921992-G-A		not specified	Uncertain significance (Nov 03, 2015)
20-48921997-C-T			Likely benign (May 27, 2022)
20-48922009-C-A			Uncertain significance (Jan 24, 2024)
20-48922022-G-A			Likely benign (Aug 19, 2022)
20-48922217-C-T			Likely benign (Jul 17, 2018)
20-48941832-C-A			Likely benign (Sep 12, 2019)
20-48941847-T-C			Likely benign (Jun 16, 2022)
20-48941865-C-T		Inborn genetic diseases	Uncertain significance (Nov 27, 2023)
20-48941869-G-T		Periventricular heterotopia with microcephaly, autosomal recessive	Uncertain significance (Jan 13, 2018)
20-48941879-A-G			Likely benign (Nov 18, 2023)

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