PRKCZ

protein-coding

protein kinase C zeta, the group of AGC family kinases

Gene summary

Protein kinase C (PKC) zeta is a member of the PKC family of serine/threonine kinases which are involved in a variety of cellular processes such as proliferation, differentiation and secretion. Unlike the classical PKC isoenzymes which are calcium-dependent, PKC zeta exhibits a kinase activity which is independent of calcium and diacylglycerol but not of phosphatidylserine. Furthermore, it is insensitive to typical PKC inhibitors and cannot be activated by phorbol ester. Unlike the classical PKC isoenzymes, it has only a single zinc finger module. These structural and biochemical properties indicate that the zeta subspecies is related to, but distinct from other isoenzymes of PKC. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002744.6

Inheritance

—

ClinVar variants

U:14B:10

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr1:2,050,411-2,185,395

External References & Databases

Transcript & Mutation Effects

hg38 • Region Span ~135.0 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRKCZ variants in ClinVar

2 Conditions Cataloged
not providedTotal: 12
not specifiedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002744.6. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
7
clinvar
2
clinvar
13
missense
7
clinvar
1
clinvar
8
nonsense
0
start loss
0
frameshift
0
splice donor/acceptor (+/-2bp)
3
clinvar
3
Total00147324
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 76 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002744.6RefSeqNP_002735.318MANE Select
ENST00000378567.8EnsemblENSP00000367830.318MANE Select
NM_001033581.3RefSeqNP_001028753.113Standard
NM_001033582.3RefSeqNP_001028754.113Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
prkczDanio rerio

Structure: dorsal longitudinal anastomotic vessel

Quality: aplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Platelet activation - Homo sapiens (human)
  • Relaxin signaling pathway - Homo sapiens (human)
  • Type II diabetes mellitus - Homo sapiens (human)
  • Insulin resistance - Homo sapiens (human)
  • AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)

Biological Process

  • microtubule cytoskeleton organization
  • positive regulation of cell-matrix adhesion
  • protein phosphorylation
  • inflammatory response
  • signal transduction

Molecular Function

  • protein kinase activity
  • protein serine/threonine kinase activity
  • protein kinase C activity
  • protein binding
  • ATP binding

Cellular Component

  • stress fiber
  • nuclear envelope
  • cytoplasm
  • endosome
  • microtubule organizing center

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000378567
Coding exons
18
Length
134926
Individuals with no LoFs
125683
Homozygous LoFs
0
Heterozygous LoFs
65
Defined
125748
p
0.000258
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.802243770.5940.00002503943
Missense (PolyPhen)51150.990.337761557
Synonymous0.2921601650.9710.00001331084
Loss of Function4.18732.90.2130.00000140389

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000560.00055rare
Latino/Admixed American0.000290.00029rare
Ashkenazi Jewish00.0absent
East Asian0.000650.00065rare
Finnish0.000140.00014rare
European (Non-Finnish)0.000250.00025rare
South Asian0.0000650.000065rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Calcium- and diacylglycerol-independent serine/threonine-protein kinase that functions in phosphatidylinositol 3-kinase (PI3K) pathway and mitogen-activated protein (MAP) kinase cascade, and is involved in NF-kappa-B activation, mitogenic signaling, cell proliferation, cell polarity, inflammatory response and maintenance of long-term potentiation (LTP). Upon lipopolysaccharide (LPS) treatment in macrophages, or following mitogenic stimuli, functions downstream of PI3K to activate MAP2K1/MEK1-MAPK1/ERK2 signaling cascade independently of RAF1 activation. Required for insulin-dependent activation of AKT3, but may function as an adapter rather than a direct activator. Upon insulin treatment may act as a downstream effector of PI3K and contribute to the activation of translocation of the glucose transporter SLC2A4/GLUT4 and subsequent glucose transport in adipocytes. In EGF-induced cells, binds and activates MAP2K5/MEK5-MAPK7/ERK5 independently of its kinase activity and can activate JUN promoter through MEF2C. Through binding with SQSTM1/p62, functions in interleukin-1 signaling and activation of NF-kappa-B with the specific adapters RIPK1 and TRAF6. Participates in TNF-dependent transactivation of NF-kappa-B by phosphorylating and activating IKBKB kinase, which in turn leads to the degradation of NF-kappa-B inhibitors. In migrating astrocytes, forms a cytoplasmic complex with PARD6A and is recruited by CDC42 to function in the establishment of cell polarity along with the microtubule motor and dynein. In association with FEZ1, stimulates neuronal differentiation in PC12 cells. In the inflammatory response, is required for the T-helper 2 (Th2) differentiation process, including interleukin production, efficient activation of JAK1 and the subsequent phosphorylation and nuclear translocation of STAT6. May be involved in development of allergic airway inflammation (asthma), a process dependent on Th2 immune response. In the NF-kappa-B-mediated inflammatory response, can relieve SETD6-dependent repression of NF-kappa-B target genes by phosphorylating the RELA subunit at 'Ser-311'. Necessary and sufficient for LTP maintenance in hippocampal CA1 pyramidal cells. In vein endothelial cells treated with the oxidant peroxynitrite, phosphorylates STK11 leading to nuclear export of STK11, subsequent inhibition of PI3K/Akt signaling, and increased apoptosis. Phosphorylates VAMP2 in vitro (PubMed:17313651). {ECO:0000269|PubMed:11035106, ECO:0000269|PubMed:12162751, ECO:0000269|PubMed:15084291, ECO:0000269|PubMed:15324659, ECO:0000269|PubMed:17313651, ECO:0000269|PubMed:18321849, ECO:0000269|PubMed:9447975}.;

Recessive Scores

pRec
0.448

Intolerance Scores

LoFtool
0.375
RVIS EVS
-0.98
RVIS percentile EVS
8.85

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.972

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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