ARFGEF2

protein-coding

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

Gene summary

ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP and is involved in Golgi transport. It contains a Sec7 domain, which may be responsible for its guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006420.3

Inheritance

AR, AD

ClinVar variants

P:29U:379B:177

Top phenotype

Heterotopia, periventricular, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr20:48,921,711-49,036,693

External References & Databases

Ensembl (ENSG00000124198)

Transcript & Mutation Effects

hg38 • Region Span ~115.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

periventricular heterotopia with microcephaly, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011966

Submitter: ClinGen

ARFGEF2 was first reported in connection to autosomal recessive periventricular heterotopia with microcephaly in 2004 (Sheen et al., 2004 PMID:14647276). Common phenotypes for individuals with ARFGEF2 - periventricular heterotopia with microcephaly include progressive microcephaly, severe GDD/ID, hypotonia, spasticity, hyperkinetic movement disorder, epilepsy, failure to thrive, cardiomyopathy, corpus callosum thinning, and putamen T2 hyperintensity/atrophy. Nine unique variants of different types (3 frameshift, 2 missense, 2 nonsense, 1 canonical splice site) reported in seven probands have been included in this curation (PMID:14647276, 19384555, 23755938, 23812912, 25160555, 26126837). The presumed mechanism is loss of function. The maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is further supported by functional alteration, protein interaction, and expression data (PMID:16320251, 14647276). In summary, there is definitive evidence to support the relationship between ARFGEF2 and autosomal recessive periventricular heterotopia with microcephaly. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Brain Malformations expert panel on 09/12/2023 (SOP Version 9).

periventricular nodular heterotopiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020341

Submitter: Orphanet

periventricular heterotopia with microcephaly, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011966

Submitter: G2P

periventricular heterotopia with microcephaly, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011966

Submitter: Labcorp Genetics (formerly Invitae)

periventricular heterotopia with microcephaly, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011966

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Heterotopia, periventricular, autosomal recessiveAR

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

Comments: 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

Refs: 12682315; 14647276; 23755938

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARFGEF2 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 485

Inborn genetic diseasesTotal: 177

Periventricular heterotopia with microcephaly, autosomal recessiveTotal: 118

not specifiedTotal: 111

ARFGEF2-related disorderTotal: 48

Intellectual disabilityTotal: 4

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

Periventricular laminar heterotopiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006420.3. 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			14 clinvar	156 clinvar	4 clinvar	174
missense			350 clinvar	16 clinvar	1 clinvar	367
nonsense	7 clinvar	6 clinvar	2 clinvar			15
start loss						0
frameshift	6 clinvar	5 clinvar	2 clinvar			13
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	11 clinvar			16
Total	15	14	379	172	5	585

Highest pathogenic variant AF is 0.000006572461

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_006420.3	RefSeq	NP_006411.2	39	MANE Select
ENST00000371917.5	Ensembl	ENSP00000360985.4	39	MANE Select
NM_001410846.1	RefSeq	NP_001397775.1	39	Standard
ENST00000679436.1	Ensembl	ENSP00000504888.1	39	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

receptor recycling
exocytosis
Golgi to plasma membrane transport
endosome organization
endomembrane system organization

Molecular Function

guanyl-nucleotide exchange factor activity
ARF guanyl-nucleotide exchange factor activity
protein binding
myosin binding
protein kinase A regulatory subunit binding

Cellular Component

Golgi membrane
trans-Golgi network
microtubule organizing center
cytosol
axonemal microtubule

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371917
Coding exons: 39
Length: 114804
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125748
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.60	731	957	0.764	0.0000560	11827
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000088	0.000079	rare
South Asian	0.00016	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.150

Intolerance Scores

LoFtool: 0.395
RVIS EVS: -2.39
RVIS percentile EVS: 1.1

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.951

Gene Damage Prediction

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