NEK8

protein-coding

NIMA related kinase 8

Gene summary

This gene encodes a member of the serine/threionine protein kinase family related to NIMA (never in mitosis, gene A) of Aspergillus nidulans. The encoded protein may play a role in cell cycle progression from G2 to M phase. Mutations in the related mouse gene are associated with a disease phenotype that closely parallels the juvenile autosomal recessive form of polycystic kidney disease in humans. [provided by RefSeq, Jul 2008]

MANE transcript

NM_178170.3

Inheritance

AD, AR

ClinVar variants

P:52U:278B:102

Top phenotype

Polycystic kidney disease 8; Renal-hepatic-pancreatic dysplasia 2

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr17:28,725,897-28,743,455

External References & Databases

Ensembl (ENSG00000160602)

Transcript & Mutation Effects

hg38 • Region Span ~17.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

renal-hepatic-pancreatic dysplasia 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014174

Submitter: PanelApp Australia

autosomal dominant polycystic kidney diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0004691

Submitter: ClinGen

*NEK8* (Never in Mitosis Gene A-related kinase 8) was first associated with monoallelic (AD) cystic kidney disease by Claus in 2023 (PMID: 37598857). *NEK8* is a serine-threonine protein kinase that is critical in cell cycle regulation through Hippo signaling. *NEK8* also appears to regulate polycystin 2 targeting to the cilia. It is required for kidney tubular cell cytoskeletal structure; renal and cardiovascular development; and for left-right symmetry. In this initial report, cysts were found first in infancy with no extrarenal manifestations in contrast to biallelic *NEK8* disease (AR). Biallelic disease is associated with nephronophthisis 9 and renal-hepatic-pancreatic dysplasia 2, where there are cysts in the kidney, liver and pancreas and often extra-renal features. Only a few variants have been reported in monoallelic *NEK8* and these are all missense changes that affect the kinase domain. In this initial report, one variant p.Arg45Trp was reported in 10 families, 6 with proven de novo mutations. One other report associated de novo *NEK8* p.Arg45Trp with infantile cystic kidneys [PMID: 36215968]. The mechanism is toxic gain of function. This gene-disease relationship is also supported by biochemical function, protein interactions and expression, as well as functional alteration in patient cells, and evidence from a cell culture model and rescue in the cell culture model. In summary, there is Strong evidence to support the relationship between *NEK8* and AD polycystic kidney disease. This has been demonstrated in both the research and the clinical diagnostic settings. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 01/08/2024 (SOP Version 10).

polycystic kidney disease 8MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0971178

Submitter: Ambry Genetics

renal-hepatic-pancreatic dysplasia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014174

Submitter: Ambry Genetics

renal-hepatic-pancreatic dysplasia 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014174

Submitter: ClinGen

*NEK8* was first reported in relation to autosomal recessive nephronophthisis (NPHP9; OMIM: 613824) by Otto et al in 2008 (PMID:8199800) and to autosomal recessive renal-hepatic-pancreatic dysplasia (RHPD2; OMIM: 615415), where there are cysts in the kidney, liver and pancreas, and bowed femora as well as a broad range of congenital cardiac anomalies, including isolated valvar abnormalities, conotruncal defects, and other congenital heart defects not typically associated with ciliopathies, by Rajagopalan et al in 2016 (PMID:26697755). Per criteria outlined by the ClinGen Lumping and Splitting Working group, we found no difference in the molecular mechanisms or inheritance pattern. Therefore, both of these disease entities were lumped into one disease entity. Null variants, splicing variants and missense variants in *NEK8* have been reported in at least 6 probands in 4 publications (PMIDs: 18199800, 26697755, 26862157, 26967905). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is biallelic loss of function. This gene-disease association is also supported by protein interactions, expression studies, functional alterations in patient and non-patient cells, non-human model organisms, cell culture models, and rescue of both a model organisms and cell culture models (PMIDs: 12421721, 18235101, 23274954, 23793029, 26967905). In summary, *NEK8* is definitively associated with autosomal recessive renal-hepatic-pancreatic dysplasia 2. This has been reportedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. There was however some discussion about whether this condition should be called a ciliopathy rather than a form of nephronophthisis since the clinical features were more consistent with a ciliopathy. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP Working Group on 9/8/2021 (SOP Version 8).

renal-hepatic-pancreatic dysplasia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014174

Submitter: G2P

nephronophthisis 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013444

Submitter: Labcorp Genetics (formerly Invitae)

nephronophthisis 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011190

Submitter: Orphanet

renal-hepatic-pancreatic dysplasia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014174

Submitter: PanelApp Australia

nephronophthisis 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013444

Submitter: G2P

renal-hepatic-pancreatic dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017417

Submitter: Orphanet

Clinical Genomic Database (CGD)

Polycystic kidney disease 8; Renal-hepatic-pancreatic dysplasia 2AD/AR

Manifestation: Cardiovascular; Gastrointestinal; Musculoskeletal; Pulmonary; Renal

Intervention: Cardiovascular; Renal

Rationale: Polycystic kidney disease 8 can involve renal disease and related sequelae (eg, hypertension), and awareness may allow medical management; Renal transplant has been described; Renal-hepatic-pancreatic dysplasia 2 can involve congenital cardiac anomalies, and awareness may allow early management

Comments: While individuals were first described with having cystic kidneys, later reports included cysts affecting other organs, such as the liver and pancreas, as well as cardiac disease

Refs: 18199800; 23418306; 26697755; 26862157; 26967905; 36215968; 37598857

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NEK8 variants in ClinVar

12 Conditions Cataloged

Nephronophthisis 9Total: 357

Renal-hepatic-pancreatic dysplasia 2Total: 165

Polycystic kidney disease 8Total: 116

Inborn genetic diseasesTotal: 109

NEK8-related disorderTotal: 82

not providedTotal: 71

not specifiedTotal: 20

Kidney disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_178170.3. 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		1 clinvar	8 clinvar	91 clinvar	2 clinvar	102
missense	2 clinvar	5 clinvar	263 clinvar	9 clinvar		279
nonsense	3 clinvar	11 clinvar				14
start loss						0
frameshift	6 clinvar	12 clinvar	3 clinvar			21
splice donor/acceptor (+/-2bp)	1 clinvar	11 clinvar	4 clinvar			16
Total	12	40	278	100	2	432

Highest pathogenic variant AF is 0.0001257754

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_178170.3	RefSeq	NP_835464.1	15	MANE Select
ENST00000268766.11	Ensembl	ENSP00000268766.6	15	MANE Select
ENST00000543014.1	Ensembl	ENSP00000465859.1	8	Standard
ENST00000579060.5	Ensembl	ENSP00000466896.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nek8	Danio rerio	Structure: pronephric proximal convoluted tubule Quality: increased diameter abnormal

Gene / Model

Organism

Observed Phenotype

nek8

Danio rerio

Structure: pronephric proximal convoluted tubule

Quality: increased diameter

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein phosphorylation
determination of left/right symmetry
heart development
animal organ morphogenesis
regulation of hippo signaling

Molecular Function

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

Cellular Component

cytoplasm
cytoskeleton
cilium
ciliary inversin compartment
ciliary base

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000268766
Coding exons: 15
Length: 17559
Individuals with no LoFs: 125668
Homozygous LoFs: 0
Heterozygous LoFs: 80
Defined: 125748
p: 0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.15	346	411	0.841	0.0000257	4458
Missense (PolyPhen)		104	147	0.70748		1582
Synonymous	-0.219	170	166	1.02	0.0000102	1473
Loss of Function	2.50	19	34.9	0.544	0.00000214	351

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00082	0.00082	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00027	0.00027	rare
South Asian	0.00065	0.00065	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for renal tubular integrity. May regulate local cytoskeletal structure in kidney tubule epithelial cells. May regulate ciliary biogenesis through targeting of proteins to the cilia (By similarity). Plays a role in organogenesis and is involved in the regulation of the Hippo signaling pathway. {ECO:0000250, ECO:0000269|PubMed:23418306}.;
Disease: DISEASE: Renal-hepatic-pancreatic dysplasia 2 (RHPD2) [MIM:615415]: A form of renal-hepatic-pancreatic dysplasia, a disease characterized by cystic malformations of the kidneys, liver, and pancreas. The pathological findings consist of multicystic dysplastic kidneys, dilated and dysgenetic bile ducts, a dysplastic pancreas with dilated ducts, cysts, fibrosis and inflammatory infiltrates. {ECO:0000269|PubMed:23418306}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.355
RVIS EVS: -1.24
RVIS percentile EVS: 5.41

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
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