PIP5K1C

phosphatidylinositol-4-phosphate 5-kinase type 1 gamma

Basic information

Region (hg38): 19:3630183-3700468

Links

ENSG00000186111 ∙ NCBI:23396 ∙ OMIM:606102 ∙ HGNC:8996 ∙ Uniprot:O60331 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• lethal congenital contracture syndrome 3 (Limited), mode of inheritance: AR
• lethal congenital contracture syndrome 3 (Strong), mode of inheritance: AR
• lethal congenital contracture syndrome 3 (Supportive), mode of inheritance: AR
• complex neurodevelopmental disorder (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lethal congenital contractural syndrome 3	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	Musculoskeletal	17701898

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PIP5K1C gene.

• not provided (3 variants)
• PIP5K1C-related neurodevelopmental disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PIP5K1C 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				23	10	33
missense	1		43	8	2	54
nonsense						0
start loss						0
frameshift	1		2			3
inframe indel						0
splice donor/acceptor (+/-2bp)	1					1
splice region				6		6
non coding			1	24	41	66
Total	3	0	46	55	53

Highest pathogenic variant AF is 0.00000657

Variants in PIP5K1C

This is a list of pathogenic ClinVar variants found in the PIP5K1C region.

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

Position	Type	Phenotype	Significance	ClinVar
19-3632973-C-G			Benign (Nov 12, 2018)
19-3633117-C-A			Benign (Nov 12, 2018)
19-3633161-T-C		PIP5K1C-related disorder	Likely benign (Aug 28, 2019)
19-3633194-A-G			Benign (Oct 21, 2019)
19-3633275-G-C			Benign (Jul 31, 2019)
19-3633442-C-T		Inborn genetic diseases	Uncertain significance (Dec 12, 2023)
19-3633444-C-T		Inborn genetic diseases	Uncertain significance (Feb 06, 2024)
19-3633446-C-T			Benign (Aug 08, 2018)
19-3633448-C-T		Inborn genetic diseases	Uncertain significance (May 04, 2022)
19-3633453-T-C		Inborn genetic diseases	Uncertain significance (Jan 29, 2024)
19-3633454-C-T		Inborn genetic diseases	Uncertain significance (May 31, 2023)
19-3633455-G-A			Likely benign (Dec 18, 2017)
19-3633461-CG-C			Uncertain significance (Apr 28, 2022)
19-3633461-C-CG			Uncertain significance (Oct 23, 2023)
19-3633462-G-A		Inborn genetic diseases	Uncertain significance (Jun 17, 2024)
19-3633466-G-A			Benign/Likely benign (Dec 01, 2022)
19-3633467-G-C			Likely benign (Aug 02, 2018)
19-3633475-C-T			Benign/Likely benign (Nov 01, 2023)
19-3633625-G-A			Benign (Sep 04, 2019)
19-3637454-C-G		PIP5K1C-related disorder	Likely benign (Nov 12, 2019)
19-3637458-C-T			Likely benign (Feb 01, 2023)
19-3637462-C-A		PIP5K1C-related disorder	Benign (Jun 25, 2019)
19-3637473-G-A		PIP5K1C-related disorder	Benign (Oct 28, 2019)
19-3637512-G-A			Benign (Dec 01, 2022)
19-3637554-C-G		PIP5K1C-related disorder	Likely benign (Feb 04, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PIP5K1C	protein_coding	protein_coding	ENST00000335312	17	70297

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.977	0.0230	125726	0	16	125742	0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.29	300	434	0.690	0.0000328	4315
Missense in Polyphen		97	195.55	0.49603		1867
Synonymous	-3.60	267	202	1.32	0.0000175	1327
Loss of Function	4.57	5	33.6	0.149	0.00000164	402

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000154	0.000152
Ashkenazi Jewish	0.00	0.00
East Asian	0.000164	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.0000810	0.0000791
Middle Eastern	0.000164	0.000163
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the phosphorylation of phosphatidylinositol 4- phosphate (PtdIns4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). PtdIns(4,5)P2 is involved in a variety of cellular processes and is the substrate to form phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), another second messenger. The majority of PtdIns(4,5)P2 is thought to occur via type I phosphatidylinositol 4-phosphate 5-kinases given the abundance of PtdIns4P. Participates in a variety of cellular processes such as vesicle mediated transport, cell adhesion, cell polarization and cell migration. Together with PIP5K1A is required for phagocytosis, but they regulate different types of actin remodeling at sequential steps. Promotes particle attachment by generating the pool of PtdIns(4,5)P2 that induces controlled actin depolymerization to facilitate Fc-gamma-R clustering. Mediates RAC1-dependent reorganization of actin filaments. Required for synaptic vesicle transport. Controls the plasma membrane pool of PtdIns(4,5)P2 implicated in synaptic vesicle endocytosis and exocytosis. Plays a role in endocytosis mediated by clathrin and AP-2 (adaptor protein complex 2). Required for clathrin-coated pits assembly at the synapse. Participates in cell junction assembly. Modulates adherens junctions formation by facilitating CDH1 trafficking. Required for focal adhesion dynamics. Modulates the targeting of talins (TLN1 and TLN2) to the plasma membrane and their efficient assembly into focal adhesions. Regulates the interaction between talins (TLN1 and TLN2) and beta-integrins. Required for uropodium formation and retraction of the cell rear during directed migration. Has a role in growth factor- stimulated directional cell migration and adhesion. Required for talin assembly into nascent adhesions forming at the leading edge toward the direction of the growth factor. Negative regulator of T-cell activation and adhesion. Negatively regulates integrin alpha-L/beta-2 (LFA-1) polarization and adhesion induced by T-cell receptor. Together with PIP5K1A has a role during embryogenesis and together with PIP5K1B may have a role immediately after birth. {ECO:0000269|PubMed:12422219, ECO:0000269|PubMed:12847086, ECO:0000269|PubMed:17261850, ECO:0000269|PubMed:17635937}.
• Disease: DISEASE: Lethal congenital contracture syndrome 3 (LCCS3) [MIM:611369]: A form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy, and congenital non-progressive joint contractures (arthrogryposis). The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth. LCCS3 patients present at birth with severe multiple joint contractures and severe muscle wasting and atrophy, mainly in the legs. Death occurs minutes to hours after birth due to respiratory insufficiency. The phenotype can be distinguished from that of LCCS1 by the absence of hydrops, fractures and multiple pterygia, and from LCCS2 by the absence of neurogenic bladder defect. {ECO:0000269|PubMed:17701898}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Focal adhesion - Homo sapiens (human);Fc gamma R-mediated phagocytosis - Homo sapiens (human);Inositol phosphate metabolism - Homo sapiens (human);Choline metabolism in cancer - Homo sapiens (human);Endocytosis - Homo sapiens (human);Regulation of actin cytoskeleton - Homo sapiens (human);Phosphatidylinositol signaling system - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);B Cell Receptor Signaling Pathway;Focal Adhesion;Regulation of Actin Cytoskeleton;Developmental Biology;D-<i>myo</i>-inositol (1,4,5)-trisphosphate biosynthesis;Signal Transduction;Vesicle-mediated transport;Membrane Trafficking;Metabolism of lipids;Inositol phosphate metabolism;Metabolism;3-phosphoinositide biosynthesis;superpathway of inositol phosphate compounds;BCR;Phosphatidylinositol phosphate metabolism;Clathrin-mediated endocytosis;SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion;Semaphorin interactions;PIP3 activates AKT signaling;Synthesis of PIPs at the plasma membrane;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;Arf6 trafficking events;PI Metabolism;Phospholipid metabolism;Axon guidance;Intracellular signaling by second messengers;Stabilization and expansion of the E-cadherin adherens junction;RAC1 signaling pathway;Nectin adhesion pathway;N-cadherin signaling events;E-cadherin signaling in the nascent adherens junction;RhoA signaling pathway (Consensus)

Recessive Scores

• pRec: 0.167

Intolerance Scores

• loftool: 0.269
• rvis_EVS: -0.31
• rvis_percentile_EVS: 32.23

Haploinsufficiency Scores

• pHI: 0.117
• hipred: Y
• hipred_score: 0.792
• ghis: 0.569

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.981

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pip5k1c
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system 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); normal 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); homeostasis/metabolism phenotype; immune system phenotype; cellular phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: phosphatidylinositol biosynthetic process;phagocytosis;regulation of phosphatidylinositol 3-kinase signaling;synaptic vesicle exocytosis;actin cytoskeleton organization;neutrophil chemotaxis;adherens junction assembly;phosphatidylinositol phosphorylation;synaptic vesicle endocytosis;membrane organization;clathrin-dependent endocytosis;cell-cell adhesion
• Cellular component: phagocytic cup;uropod;nucleoplasm;cytosol;focal adhesion;endosome membrane;ruffle membrane;presynapse
• Molecular function: protein binding;ATP binding;1-phosphatidylinositol-4-phosphate 5-kinase activity;1-phosphatidylinositol-3-phosphate 4-kinase activity;phosphatidylinositol-3,4-bisphosphate 5-kinase activity