NEK2
protein-codingNIMA related kinase 2, the group of Protein phosphatase 1 regulatory subunits
Gene summary
This gene encodes a serine/threonine-protein kinase that is involved in mitotic regulation. This protein is localized to the centrosome, and undetectable during G1 phase, but accumulates progressively throughout the S phase, reaching maximal levels in late G2 phase. Alternatively spliced transcript variants encoding different isoforms with distinct C-termini have been noted for this gene. [provided by RefSeq, Feb 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014256
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014256
Submitter: G2P
Inheritance Pattern: Unknown
Disease ID:MONDO:0014256
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014256
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NEK2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002497.4. 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 | 2 | 64 | 1 | 67 | ||
| missense | 2 | 160 | 6 | 168 | ||
| nonsense | 11 | 11 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 10 | 13 | |||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 0 | 6 | 188 | 70 | 1 | 265 |
Highest pathogenic variant AF is 0.000002748763
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002488.1 | 8 | MANE Select | |
| Ensembl | ENSP00000355966.4 | 8 | MANE Select | |
| RefSeq | NP_001191111.1 | 8 | Standard | |
| RefSeq | NP_001191112.1 | 7 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nek2 | Danio rerio | Structure: retinal rod cell Quality: malformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Regulation of PLK1 Activity at G2/M Transition
- Recruitment of mitotic centrosome proteins and complexes
- Loss of Nlp from mitotic centrosomes
- Loss of proteins required for interphase microtubule organization from the centrosome
- Centrosome maturation
Biological Process
- mitotic sister chromatid segregation
- G2/M transition of mitotic cell cycle
- mitotic cell cycle
- blastocyst development
- protein phosphorylation
Molecular Function
- protein kinase activity
- protein serine/threonine kinase activity
- protein binding
- ATP binding
- protein phosphatase binding
Cellular Component
- kinetochore
- condensed chromosome kinetochore
- condensed nuclear chromosome
- spindle pole
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000366999
- Coding exons
- 8
- Length
- 12847
- Individuals with no LoFs
- 125653
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 95
- Defined
- 125748
- p
- 0.000378
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.30 | 188 | 245 | 0.767 | 0.0000135 | 2904 |
| Missense (PolyPhen) | 55 | 83.402 | 0.65946 | 910 | ||
| Synonymous | 0.206 | 87 | 89.5 | 0.972 | 0.00000463 | 839 |
| Loss of Function | 2.28 | 14 | 26.8 | 0.523 | 0.00000188 | 286 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00077 | 0.00074 | rare |
| Latino/Admixed American | 0.00024 | 0.00023 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00058 | 0.00055 | rare |
| South Asian | 0.00026 | 0.00026 | rare |
| Other | 0.00034 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and NINL, resulting in their displacement from the centrosomes. Regulates kinetochore microtubule attachment stability in mitosis via phosphorylation of NDC80. Involved in regulation of mitotic checkpoint protein complex via phosphorylation of CDC20 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGO1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Phosphorylates CEP68 and CNTLN directly or indirectly (PubMed:24554434). NEK2-mediated phosphorylation of CEP68 promotes CEP68 dissociation from the centrosome and its degradation at the onset of mitosis (PubMed:25704143). Involved in the regulation of centrosome disjunction (PubMed:26220856). {ECO:0000269|PubMed:11742531, ECO:0000269|PubMed:12857871, ECO:0000269|PubMed:14978040, ECO:0000269|PubMed:15358203, ECO:0000269|PubMed:15388344, ECO:0000269|PubMed:17283141, ECO:0000269|PubMed:17621308, ECO:0000269|PubMed:17626005, ECO:0000269|PubMed:18086858, ECO:0000269|PubMed:18297113, ECO:0000269|PubMed:20034488, ECO:0000269|PubMed:21076410, ECO:0000269|PubMed:24554434, ECO:0000269|PubMed:25704143, ECO:0000269|PubMed:26220856}.; FUNCTION: Isoform 2: Not present in the nucleolus and, in contrast to isoform 1, does not phosphorylate and activate NEK11 in G1/S- arrested cells. {ECO:0000269|PubMed:15161910}.;
- Disease
- DISEASE: Retinitis pigmentosa 67 (RP67) [MIM:615565]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:24043777}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.205
Intolerance Scores
- LoFtool
- 0.604
- RVIS EVS
- -0.31
- RVIS percentile EVS
- 31.93
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.995
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |