INPP5K

protein-coding

inositol polyphosphate-5-phosphatase K, the group of Phosphoinositide phosphatases

Gene summary

This gene encodes a protein with 5-phosphatase activity toward polyphosphate inositol. The protein localizes to the cytosol in regions lacking actin stress fibers. It is thought that this protein may negatively regulate the actin cytoskeleton. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

MANE transcript

NM_016532.4

Inheritance

ClinVar variants

P:17U:91B:50

Top phenotype

Muscular dystrophy, congenital, with cataracts and intellectual disability

gnomAD constraint

pLI —, LoF o/e 0.48

Max pathogenic AF

—

Genomic locus

chr17:1,494,577-1,516,742

External References & Databases

Ensembl (ENSG00000132376)

Transcript & Mutation Effects

hg38 • Region Span ~22.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

muscular dystrophy, congenital, with cataracts and impaired intellectual developmentSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024607

Submitter: G2P

muscular dystrophy, congenital, with cataracts and impaired intellectual developmentSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024607

Submitter: Ambry Genetics

muscular dystrophy, congenital, with cataracts and impaired intellectual developmentSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024607

Submitter: Labcorp Genetics (formerly Invitae)

muscular dystrophy, congenital, with cataracts and impaired intellectual developmentSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024607

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Muscular dystrophy, congenital, with cataracts and intellectual disabilityAR

Manifestation: Musculoskeletal; Neurologic; Ophthalmologic

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: 28190456; 28190459

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to INPP5K variants in ClinVar

12 Conditions Cataloged

Inborn genetic diseasesTotal: 73

not providedTotal: 57

Congenital muscular dystrophy with cataracts and intellectual disabilityTotal: 32

not specifiedTotal: 22

INPP5K-related disorderTotal: 17

INPP5K-related disordersTotal: 3

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1Total: 2

Congenital myopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016532.4. 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			3 clinvar	30 clinvar	3 clinvar	36
missense	4 clinvar	6 clinvar	82 clinvar	13 clinvar	4 clinvar	109
nonsense		1 clinvar	2 clinvar			3
start loss						0
frameshift	2 clinvar	2 clinvar				4
splice donor/acceptor (+/-2bp)		2 clinvar	4 clinvar			6
Total	6	11	91	43	7	158

Highest pathogenic variant AF is 0.000019848385

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016532.4	RefSeq	NP_057616.2	12	MANE Select
ENST00000421807.7	Ensembl	ENSP00000413937.2	12	MANE Select
NM_001135642.2	RefSeq	NP_001129114.1	10	Standard
NM_130766.3	RefSeq	NP_570122.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
inpp5ka	Danio rerio	Structure: skeletal muscle Quality: structure abnormal

Gene / Model

Organism

Observed Phenotype

inpp5ka

Danio rerio

Structure: skeletal muscle

Quality: structure

abnormal

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)
Insulin signaling pathway - Homo sapiens (human)
Notch Signaling Pathway
Notch Signaling Pathway

Biological Process

negative regulation of protein phosphorylation
regulation of glycogen biosynthetic process
negative regulation of protein kinase activity
phosphatidylinositol biosynthetic process
G protein-coupled receptor signaling pathway

Molecular Function

phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity
inositol-polyphosphate 5-phosphatase activity
vasopressin receptor activity
protein binding
inositol bisphosphate phosphatase activity

Cellular Component

ruffle
nucleus
cytoplasm
endoplasmic reticulum
trans-Golgi network

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000421807
Coding exons: 12
Length: 22318
Individuals with no LoFs: 125724
Homozygous LoFs: 0
Heterozygous LoFs: 24
Defined: 125748
p: 0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.601	248	276	0.898	0.0000166	2953
Missense (PolyPhen)		88	108.67	0.8098		1255
Synonymous	0.469	113	120	0.945	0.00000803	848
Loss of Function	2.34	11	23.1	0.475	0.00000107	260

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inositol 5-phosphatase which acts on inositol 1,4,5- trisphosphate, inositol 1,3,4,5-tetrakisphosphate, phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. Has 6-fold higher affinity for phosphatidylinositol 4,5-bisphosphate than for inositol 1,4,5- trisphosphate (PubMed:10753883). Negatively regulates assembly of the actin cytoskeleton. Controls insulin-dependent glucose uptake among inositol 3,4,5-trisphosphate phosphatases; therefore, is the specific regulator for insulin signaling in skeletal muscle (By similarity). {ECO:0000250|UniProtKB:Q8C5L6, ECO:0000269|PubMed:10753883, ECO:0000269|PubMed:28190456, ECO:0000269|PubMed:28190459}.;

Recessive Scores

pRec: 0.111

Intolerance Scores

LoFtool: 0.0696
RVIS EVS: -0.07
RVIS percentile EVS: 48.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.957

Gene Damage Prediction

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