NEK9

protein-coding

NIMA related kinase 9

Gene summary

This gene encodes a member of the NimA (never in mitosis A) family of serine/threonine protein kinases. The encoded protein is activated in mitosis and, in turn, activates other family members during mitosis. This protein also mediates cellular processes that are essential for interphase progression. [provided by RefSeq, Jul 2016]

MANE transcript

NM_033116.6

Inheritance

ClinVar variants

P:26U:142B:33

Top phenotype

Arthrogryposis, Perthes disease, and upward gaze palsy; Lethal congenital contracture syndrome 10

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr14:75,079,353-75,127,344

External References & Databases

Ensembl (ENSG00000119638)

Transcript & Mutation Effects

hg38 • Region Span ~48.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

NEK9-related lethal skeletal dysplasiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014870

Submitter: Ambry Genetics

NEK9-related lethal skeletal dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014870

Submitter: Orphanet

NEK9-related lethal skeletal dysplasiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014870

Submitter: PanelApp Australia

NEK9-related lethal skeletal dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014870

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Arthrogryposis, Perthes disease, and upward gaze palsy; Lethal congenital contracture syndrome 10AR

Manifestation: 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: 21271645; 26633546; 26908619

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NEK9 variants in ClinVar

13 Conditions Cataloged

Inborn genetic diseasesTotal: 121

not providedTotal: 51

NEK9-related disorderTotal: 24

Arthrogryposis, Perthes disease, and upward gaze palsyTotal: 13

NEK9-related lethal skeletal dysplasiaTotal: 13

not specifiedTotal: 7

Nevus comedonicus syndromeTotal: 5

Goldberg-Shprintzen syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033116.6. 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	18 clinvar	3 clinvar	24
missense	1 clinvar	5 clinvar	132 clinvar	8 clinvar	4 clinvar	150
nonsense	6 clinvar	3 clinvar	2 clinvar			11
start loss						0
frameshift	3 clinvar	3 clinvar	1 clinvar			7
splice donor/acceptor (+/-2bp)		5 clinvar	4 clinvar			9
Total	10	16	142	26	7	201

Highest pathogenic variant AF is 0.0008312448

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033116.6	RefSeq	NP_149107.4	22	MANE Select
ENST00000238616.10	Ensembl	ENSP00000238616.5	22	MANE Select
NM_001329237.2	RefSeq	NP_001316166.1	22	Standard
NM_001329238.2	RefSeq	NP_001316167.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nuclear Pore Complex (NPC) Disassembly
Activation of NIMA Kinases NEK9, NEK6, NEK7
Nuclear Envelope Breakdown
Mitotic Prophase
M Phase

Biological Process

protein phosphorylation
mitotic nuclear envelope disassembly
cell division

Molecular Function

protein serine/threonine kinase activity
protein binding
ATP binding
protein kinase binding
metal ion binding

Cellular Component

nucleus
centrosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000238616
Coding exons: 22
Length: 45226
Individuals with no LoFs: 125588
Homozygous LoFs: 0
Heterozygous LoFs: 160
Defined: 125748
p: 0.000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.50	365	527	0.693	0.0000276	6330
Missense (PolyPhen)		78	186.92	0.41729		2238
Synonymous	0.409	192	199	0.963	0.0000105	1944
Loss of Function	2.40	36	55.3	0.651	0.00000304	638

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00050	0.00049	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.0014	0.0014	notable
East Asian	0.00016	0.00016	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00099	0.00098	rare
South Asian	0.00016	0.00016	rare
Other	0.0013	0.0013	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Pleiotropic regulator of mitotic progression, participating in the control of spindle dynamics and chromosome separation. Phosphorylates different histones, myelin basic protein, beta-casein, and BICD2. Phosphorylates histone H3 on serine and threonine residues and beta-casein on serine residues. Important for G1/S transition and S phase progression. Phosphorylates NEK6 and NEK7 and stimulates their activity by releasing the autoinhibitory functions of Tyr-108 and Tyr-97 respectively. {ECO:0000269|PubMed:12840024, ECO:0000269|PubMed:14660563, ECO:0000269|PubMed:19941817}.;
Disease: DISEASE: Lethal congenital contracture syndrome 10 (LCCS10) [MIM:617022]: 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. 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. {ECO:0000269|PubMed:26908619}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Nevus comedonicus (NC) [MIM:617025]: A rare type of epidermal nevus characterized by closely arranged, dilated, plugged follicular ostia in a honeycomb pattern. The plugged ostia contain lamellated keratinaceous material, and their appearance resembles black dots. NC may be non-pyogenic with an acne-like appearance or associated with the formation of cysts, papules, pustules, and abscesses. Most commonly it affects the face and neck area and, by exception, other anatomical regions, including genital area, palms, and soles. NC lesions might present with various patterns of distribution: unilateral, bilateral, linear, interrupted, segmental, or blaschkoid. {ECO:0000269|PubMed:27153399}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Arthrogryposis, Perthes disease, and upward gaze palsy (APUG) [MIM:614262]: An autosomal recessive, syndromic form of arthrogryposis, a disease characterized by persistent joints flexure or contracture. APUG patients manifest an unusual combination of arthrogryposis, upward gaze palsy, and avascular necrosis of the hip (Perthes disease). {ECO:0000269|PubMed:26633546}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.317

Intolerance Scores

LoFtool: 0.453
RVIS EVS: -0.42
RVIS percentile EVS: 25.83

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.965

Gene Damage Prediction

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