NEK1

protein-coding

NIMA related kinase 1

Gene summary

The protein encoded by this gene is a serine/threonine kinase involved in cell cycle regulation. The encoded protein is found in a centrosomal complex with FEZ1, a neuronal protein that plays a role in axonal development. Defects in this gene are a cause of polycystic kidney disease (PKD). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

MANE transcript

NM_001199397.3

Inheritance

AD, AR, Digenic

ClinVar variants

P:125U:428B:195

Top phenotype

Orofaciodigital syndrome II; Short-rib thoracic dysplasia 6 with or without polydactyly

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr4:169,369,704-169,612,632

External References & Databases

Ensembl (ENSG00000137601)

Transcript & Mutation Effects

hg38 • Region Span ~242.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amyotrophic lateral sclerosis, susceptibility to, 24STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054750

Submitter: Labcorp Genetics (formerly Invitae)

short-rib thoracic dysplasia 6 with or without polydactylySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009894

Submitter: PanelApp Australia

amyotrophic lateral sclerosis, susceptibility to, 24STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054750

Submitter: PanelApp Australia

amyotrophic lateral sclerosis, susceptibility to, 24DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0054750

Submitter: ClinGen

*NEK1* was first reported in relation to autosomal dominant amyotrophic lateral sclerosis (ALS) type 24 in 2015 (Cirulli et al., PMID: 25700176). *NEK1* encodes never in mitosis gene a-related kinase 1 (Nek1) and has a role in cell cycle control and cilia regulation. *NEK1* has also been associated with autosomal recessive short-rib thoracic dysplasia 6 with or without polydactyly. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism, inheritance pattern, and phenotypic variability between this disease and ALS type 24. Therefore, the following disease entities have been split into two disease entities: ALS type 24 (OMIM: 617892) and short-rib thoracic dysplasia 6 with or without polydactyly (OMIM:263520). The association between *NEK1* and ALS was first established in an exome-wide gene burden analysis that identified an association between loss of function rare variants in the gene and the phenotype based on the exome sequencing of 2874 ALS cases and 6405 controls (Cirulli et al., PMID: 25700176). This curation also includes an additional 13 case-control analyses from 11 publications (PMIDs: 25700176, 26945885, 27455347, 28935222, 29149916, 30940688, 30976013, 31768050, 32920598, 34544842, 31475037). Additionally, 40 variants, including missense, nonsense, frameshift, and splicing variants, reported in 40 probands in 10 publications (PMIDs: 26945885, 28935222, 30093141, 31108397, 31475037, 32462798, 32772750, 32920598, 33445179, 34564799) are included in this curation. Based on this curation, the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function, although missense variants have also been reported in ALS probands. This gene-disease association is also supported by experimental evidence describing physical interaction with other known ALS associated genes and functional alterations in mutated patient cells (PMIDs: 30992335, 29929116, 25700176), although experimental evidence remains marginal overall. In summary, *NEK1* is definitively associated with autosomal dominant ALS type 24. This has been repeatedly demonstrated in both the research and clinical diagnostic settings as shown by the genetic evidence and has been upheld over time. Although, we believe that more experimental evidence is needed to gain a greater understanding of the involvement of *NEK1* in ALS pathophysiology. It is important to understand that in the clinical diagnostic setting the identification of missense variants of uncertain significance may be common and variant interpretation must be completed with caution. This classification was approved by the ClinGen ALS GCEP on 02/24/2021 (SOPv8).

short rib-polydactyly syndrome, Majewski typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019662

Submitter: Orphanet

orofaciodigital syndrome type IISUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009642

Submitter: Orphanet

amyotrophic lateral sclerosis, susceptibility to, 24MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0054750

Submitter: Genomics England PanelApp

short-rib thoracic dysplasia 6 with or without polydactylyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009894

Submitter: G2P

short-rib thoracic dysplasia 6 with or without polydactylySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009894

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Orofaciodigital syndrome II; Short-rib thoracic dysplasia 6 with or without polydactylyAR/Digenic

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Renal

Intervention: Audiologic/Otolaryngologic; Cardiovascular

Rationale: Orofaciodigital syndrome II can include hearing loss, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Short-rib thoracic dysplasia 6 with or without polydactyly can involve congenital cardiac anomalies, and awareness may allow early management

Comments: Heterozygous (digenic) variants in both NEK1 and DYNC2H1 can result in disease

Refs: 21211617; 22499340; 22795106; 22499340; 26945885; 27455347

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NEK1 variants in ClinVar

18 Conditions Cataloged

Short-rib thoracic dysplasia 6 with or without polydactylyTotal: 710

not providedTotal: 186

NEK1-related disorderTotal: 154

Inborn genetic diseasesTotal: 143

not specifiedTotal: 56

Amyotrophic lateral sclerosis, susceptibility to, 24Total: 37

Motor neuron diseaseTotal: 18

Connective tissue disorderTotal: 18

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001199397.3. 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			10 clinvar	147 clinvar	2 clinvar	159
missense	3 clinvar	8 clinvar	405 clinvar	43 clinvar	3 clinvar	462
nonsense	17 clinvar	19 clinvar	4 clinvar			40
start loss		1 clinvar				1
frameshift	26 clinvar	25 clinvar	5 clinvar			56
splice donor/acceptor (+/-2bp)	2 clinvar	24 clinvar	4 clinvar			30
Total	48	77	428	190	5	748

Highest pathogenic variant AF is 0.00020822926

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 74 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001199397.3	RefSeq	NP_001186326.1	34	MANE Select
ENST00000507142.6	Ensembl	ENSP00000424757.2	34	MANE Select
NM_001199398.3	RefSeq	NP_001186327.1	33	Standard
NM_001199399.3	RefSeq	NP_001186328.1	31	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nek1	Danio rerio	Structure: photoreceptor cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

nek1

Danio rerio

Structure: photoreceptor cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein phosphorylation
cellular response to DNA damage stimulus
cell cycle
peptidyl-tyrosine phosphorylation
signal transduction by protein phosphorylation

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
protein tyrosine kinase activity
protein binding
ATP binding

Cellular Component

pericentriolar material
nucleus
cytoplasm
centrosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000507142
Coding exons: 34
Length: 219355
Individuals with no LoFs: 124563
Homozygous LoFs: 0
Heterozygous LoFs: 91
Defined: 124654
p: 0.000365

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.07	542	617	0.879	0.0000302	8416
Missense (PolyPhen)		154	207.39	0.74257		2943
Synonymous	-0.138	213	210	1.01	0.0000106	2303
Loss of Function	2.54	51	74.7	0.683	0.00000381	1004

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00033	0.00032	rare
Latino/Admixed American	0.00044	0.00038	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00035	0.00033	rare
Finnish	0.000099	0.000093	rare
European (Non-Finnish)	0.00045	0.00043	rare
South Asian	0.00043	0.00042	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Phosphorylates serines and threonines, but also appears to possess tyrosine kinase activity (PubMed:20230784). Involved in DNA damage checkpoint control and for proper DNA damage repair (PubMed:20230784). In response to injury that includes DNA damage, NEK1 phosphorylates VDAC1 to limit mitochondrial cell death (PubMed:20230784). May be implicated in the control of meiosis (By similarity). Involved in cilium assembly (PubMed:21211617). {ECO:0000250|UniProtKB:P51954, ECO:0000269|PubMed:20230784, ECO:0000269|PubMed:21211617}.;
Disease: DISEASE: Amyotrophic lateral sclerosis 24 (ALS24) [MIM:617892]: A form of amyotrophic lateral sclerosis, a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. {ECO:0000269|PubMed:26945885, ECO:0000269|PubMed:27455347}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0930

Intolerance Scores

LoFtool: 0.968
RVIS EVS: -0.08
RVIS percentile EVS: 47.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.329

Gene Damage Prediction

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