PLK4

protein-coding

polo like kinase 4

Gene summary

This gene encodes a member of the polo family of serine/threonine protein kinases. The protein localizes to centrioles, complex microtubule-based structures found in centrosomes, and regulates centriole duplication during the cell cycle. Three alternatively spliced transcript variants that encode different protein isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

Previous symbols:

STK18

MANE transcript

NM_014264.5

Inheritance

ClinVar variants

P:40U:347B:177

Top phenotype

Microcephaly and chorioretinopathy, autosomal recessive 2

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr4:127,880,893-127,899,224

External References & Databases

Ensembl (ENSG00000142731)

Transcript & Mutation Effects

hg38 • Region Span ~18.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly and chorioretinopathy 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014516

Submitter: Illumina

microcephaly and chorioretinopathy 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009624

Submitter: Orphanet

microcephaly and chorioretinopathy 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014516

Submitter: G2P

microcephaly and chorioretinopathy 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014516

Submitter: PanelApp Australia

microcephaly and chorioretinopathy 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014516

Submitter: Labcorp Genetics (formerly Invitae)

Seckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019342

Submitter: Orphanet

Clinical Genomic Database (CGD)

Microcephaly and chorioretinopathy, autosomal recessive 2AR

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: 25320347; 25344692

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLK4 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 610

Inborn genetic diseasesTotal: 137

not specifiedTotal: 62

PLK4-related disorderTotal: 23

Microcephaly and chorioretinopathy 2Total: 14

Retinal dystrophyTotal: 3

PLK4-related microcephaly and growth failure with or without ocular featuresTotal: 2

Optic atrophyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014264.5. 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			6 clinvar	150 clinvar	2 clinvar	158
missense			332 clinvar	23 clinvar	2 clinvar	357
nonsense	8 clinvar	3 clinvar	2 clinvar			13
start loss						0
frameshift	13 clinvar	9 clinvar	1 clinvar			23
splice donor/acceptor (+/-2bp)		7 clinvar	6 clinvar			13
Total	21	19	347	173	4	564

Highest pathogenic variant AF is 0.0000365551

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014264.5	RefSeq	NP_055079.3	16	MANE Select
ENST00000270861.10	Ensembl	ENSP00000270861.5	16	MANE Select
NM_001190799.2	RefSeq	NP_001177728.1	15	Standard
NM_001190801.2	RefSeq	NP_001177730.1	15	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
plk4	Danio rerio	Structure: photoreceptor cell Quality: absent abnormal

Gene / Model

Organism

Observed Phenotype

plk4

Danio rerio

Structure: photoreceptor cell

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

FoxO signaling pathway - Homo sapiens (human)
Retinoblastoma (RB) in Cancer
Regulation of PLK1 Activity at G2/M Transition
Recruitment of mitotic centrosome proteins and complexes
Loss of Nlp from mitotic centrosomes

Biological Process

G2/M transition of mitotic cell cycle
protein phosphorylation
centriole replication
regulation of G2/M transition of mitotic cell cycle
positive regulation of centriole replication

Molecular Function

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

Cellular Component

XY body
nucleolus
centrosome
centriole
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000270861
Coding exons: 16
Length: 18335
Individuals with no LoFs: 125691
Homozygous LoFs: 0
Heterozygous LoFs: 56
Defined: 125747
p: 0.000223

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.800	447	497	0.899	0.0000236	6395
Missense (PolyPhen)		130	198.85	0.65376		2555
Synonymous	-1.31	187	166	1.13	0.00000770	1805
Loss of Function	3.85	17	44.8	0.379	0.00000235	585

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00054	0.00043	rare
Latino/Admixed American	0.00028	0.00023	rare
Ashkenazi Jewish	0.00047	0.00030	rare
East Asian	0.00018	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00021	0.00020	rare
South Asian	0.00031	0.00029	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine-protein kinase that plays a central role in centriole duplication. Able to trigger procentriole formation on the surface of the parental centriole cylinder, leading to the recruitment of centriole biogenesis proteins such as SASS6, CENPJ/CPAP, CCP110, CEP135 and gamma-tubulin. When overexpressed, it is able to induce centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole during S phase. Phosphorylates 'Ser-151' of FBXW5 during the G1/S transition, leading to inhibit FBXW5 ability to ubiquitinate SASS6. Its central role in centriole replication suggests a possible role in tumorigenesis, centrosome aberrations being frequently observed in tumors. Also involved in deuterosome-mediated centriole amplification in multiciliated that can generate more than 100 centrioles. Also involved in trophoblast differentiation by phosphorylating HAND1, leading to disrupt the interaction between HAND1 and MDFIC and activate HAND1. Phosphorylates CDC25C and CHEK2. Required for the recruitment of STIL to the centriole and for STIL-mediated centriole amplification (PubMed:22020124). {ECO:0000269|PubMed:16244668, ECO:0000269|PubMed:16326102, ECO:0000269|PubMed:17681131, ECO:0000269|PubMed:18239451, ECO:0000269|PubMed:19164942, ECO:0000269|PubMed:21725316, ECO:0000269|PubMed:22020124, ECO:0000269|PubMed:27796307}.;
Disease: DISEASE: Microcephaly and chorioretinopathy, autosomal recessive, 2 (MCCRP2) [MIM:616171]: A severe disorder characterized by microcephaly, delayed psychomotor development, growth retardation with dwarfism, and ocular abnormalities. {ECO:0000269|PubMed:25344692}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.246

Intolerance Scores

LoFtool: 0.831
RVIS EVS: -0.31
RVIS percentile EVS: 32.23

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.970

Gene Damage Prediction

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