PI4K2A

protein-coding

phosphatidylinositol 4-kinase type 2 alpha

Gene summary

Phosphatidylinositolpolyphosphates (PtdInsPs) are centrally involved in many biologic processes, ranging from cell growth and organization of the actin cytoskeleton to endo- and exocytosis. PI4KII phosphorylates PtdIns at the D-4 position, an essential step in the biosynthesis of PtdInsPs (Barylko et al., 2001 [PubMed 11244087]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_018425.4

Inheritance

ClinVar variants

P:3U:49

Top phenotype

Neurodevelopmental disorder with hyperkinetic movements, seizures and structural brain abnormalities

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr10:97,640,671-97,676,434

External References & Databases

Ensembl (ENSG00000155252)

Transcript & Mutation Effects

hg38 • Region Span ~35.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with hyperkinetic movements, seizures, and structural brain abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0958240

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with hyperkinetic movements, seizures and structural brain abnormalitiesAR

Manifestation: Craniofacial; Musculoskeletal; 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

Refs: 30564627; 32418222; 35880319

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PI4K2A variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 45

Neurodevelopmental disorder with hyperkinetic movements, seizures, and structural brain abnormalitiesTotal: 3

not providedTotal: 1

PI4K2A-related conditionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018425.4. 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						0
missense			48 clinvar			48
nonsense	2 clinvar	1 clinvar	1 clinvar			4
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	2	1	49	0	0	52

Highest pathogenic variant AF is 0.0000020681669

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018425.4	RefSeq	NP_060895.1	9	MANE Select
ENST00000370631.4	Ensembl	ENSP00000359665.3	9	MANE Select
ENST00000880057.1	Ensembl	ENSP00000550116.1	8	Standard
ENST00000880057.2	Ensembl	ENSP00000550116.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inositol phosphate metabolism - Homo sapiens (human)
Phosphatidylinositol signaling system - Homo sapiens (human)
Thymic Stromal LymphoPoietin (TSLP) Signaling Pathway
Wnt Signaling Pathway
D-<i>myo</i>-inositol (1,4,5)-trisphosphate biosynthesis

Biological Process

basophil degranulation
phosphatidylinositol biosynthetic process
Golgi organization
endosome organization
phosphatidylinositol phosphorylation

Molecular Function

magnesium ion binding
1-phosphatidylinositol 4-kinase activity
protein binding
ATP binding
AP-3 adaptor complex binding

Cellular Component

mitochondrion
lysosomal membrane
endosome
trans-Golgi network
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370631
Coding exons: 9
Length: 92061
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125746
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.89	129	260	0.496	0.0000143	3086
Missense (PolyPhen)		30	97.665	0.30717		1194
Synonymous	1.97	77	102	0.752	0.00000522	960
Loss of Function	3.67	4	23.0	0.174	0.00000113	254

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Membrane-bound phosphatidylinositol-4 kinase (PI4- kinase) that catalyzes the phosphorylation of phosphatidylinositol (PI) to phosphatidylinositol 4-phosphate (PI4P), a lipid that plays important roles in endocytosis, Golgi function, protein sorting and membrane trafficking and is required for prolonged survival of neurons. Besides, phosphorylation of phosphatidylinositol (PI) to phosphatidylinositol 4-phosphate (PI4P) is the first committed step in the generation of phosphatidylinositol 4,5-bisphosphate (PIP2), a precursor of the second messenger inositol 1,4,5-trisphosphate (InsP3). {ECO:0000269|PubMed:11279162, ECO:0000269|PubMed:16443754, ECO:0000269|PubMed:20388919, ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:24675427, ECO:0000269|PubMed:25168678, ECO:0000305}.;

Intolerance Scores

LoFtool: 0.102
RVIS EVS: 0.55
RVIS percentile EVS: 81.38

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.876

Gene Damage Prediction

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