GeneBe

CLP1

protein-coding

cleavage factor polyribonucleotide kinase subunit 1

Gene summary

This gene encodes a member of the Clp1 family. The encoded protein is a multifunctional kinase which is a component of the tRNA splicing endonuclease complex and a component of the pre-mRNA cleavage complex II. This protein is implicated in tRNA, mRNA, and siRNA maturation. Mutations in this gene are associated with pontocerebellar hypoplasia type 10 (PCH10). Alternatively splice transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

MANE transcript

NM_006831.3

Inheritance

AR

ClinVar variants

P:5U:71B:47

Top phenotype

Pontocerebellar hypoplasia type 10

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr11:57,648,188-57,661,865

External References & Databases

Ensembl (ENSG00000172409)NCBI Gene (10978)OMIM (608757)HGNC:16999GenCCUniProt (Q92989)AlphaFoldClinVar (CLP1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~13.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pontocerebellar hypoplasia type 10SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014349

Submitter: Orphanet

pontocerebellar hypoplasia type 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014349

Submitter: G2P

pontocerebellar hypoplasia type 10LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014349

Submitter: Labcorp Genetics (formerly Invitae)

pontocerebellar hypoplasia type 10MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014349

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Pontocerebellar hypoplasia type 10AR

Manifestation: Craniofacial; Neurologic

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: 24766809; 24766810; 29307788Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLP1 variants in ClinVar

6 Conditions Cataloged
not providedTotal: 83
Inborn genetic diseasesTotal: 38
Pontocerebellar hypoplasia type 10Total: 15
not specifiedTotal: 7
CLP1-related disorderTotal: 6
Pontoneocerebellar hypoplasiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006831.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
38
clinvar
5
clinvar
 44
missense
1
clinvar
69
clinvar
4
clinvar
 74
nonsense
3
clinvar
1
clinvar
 4
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
0
Total0571425123

Highest pathogenic variant AF is 0.000041726864

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006831.3RefSeqNP_006822.12MANE Select
ENST00000533682.2EnsemblENSP00000434995.12MANE Select
NM_001142597.2RefSeqNP_001136069.12Standard
ENST00000302731.4EnsemblENSP00000304704.42Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
clp1Danio rerio

Structure: motor neuron

Quality: broken

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • mRNA surveillance pathway - Homo sapiens (human)
  • mRNA Processing
  • tRNA processing
  • Gene expression (Transcription)
  • RNA Polymerase II Transcription

Biological Process

  • mRNA splicing, via spliceosome
  • termination of RNA polymerase II transcription
  • mRNA polyadenylation
  • tRNA splicing, via endonucleolytic cleavage and ligation
  • phosphorylation

Molecular Function

  • ATP binding
  • ATP-dependent polydeoxyribonucleotide 5'-hydroxyl-kinase activity
  • polydeoxyribonucleotide kinase activity
  • ATP-dependent polyribonucleotide 5'-hydroxyl-kinase activity

Cellular Component

  • tRNA-intron endonuclease complex
  • nucleus
  • nucleoplasm
  • cytosol
  • mRNA cleavage factor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000533682
Coding exons
2
Length
12876
Individuals with no LoFs
125730
Homozygous LoFs
0
Heterozygous LoFs
18
Defined
125748
p
0.0000716
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.251522530.6010.00001542751
Missense (PolyPhen)4581.3440.55321825
Synonymous1.367793.70.8220.00000475919
Loss of Function2.71415.50.2580.00000128144

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian0.000160.00016rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000790.000079rare
South Asian0.000130.00013rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Polynucleotide kinase that can phosphorylate the 5'- hydroxyl groups of double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), double-stranded DNA (dsDNA) and double-stranded DNA:RNA hybrids. dsRNA is phosphorylated more efficiently than dsDNA, and the RNA component of a DNA:RNA hybrid is phosphorylated more efficiently than the DNA component. Plays a key role in both tRNA splicing and mRNA 3'-end formation. Component of the tRNA splicing endonuclease complex: phosphorylates the 5'-terminus of the tRNA 3'-exon during tRNA splicing; this phosphorylation event is a prerequisite for the subsequent ligation of the two exon halves and the production of a mature tRNA (PubMed:24766809, PubMed:24766810). Its role in tRNA splicing and maturation is required for cerebellar development (PubMed:24766809, PubMed:24766810). Component of the pre-mRNA cleavage complex II (CF-II), which seems to be required for mRNA 3'-end formation. Also phosphorylates the 5'-terminus of exogenously introduced short interfering RNAs (siRNAs), which is a necessary prerequisite for their incorporation into the RNA-induced silencing complex (RISC). However, endogenous siRNAs and microRNAs (miRNAs) that are produced by the cleavage of dsRNA precursors by DICER1 already contain a 5'-phosphate group, so this protein may be dispensible for normal RNA-mediated gene silencing. {ECO:0000269|PubMed:17495927, ECO:0000269|PubMed:18648070, ECO:0000269|PubMed:24766809, ECO:0000269|PubMed:24766810}.;
Disease
DISEASE: Pontocerebellar hypoplasia 10 (PCH10) [MIM:615803]: A form of pontocerebellar hypoplasia, a disorder characterized by structural defects of the pons and cerebellum, evident upon brain imaging. PCH10 features include cortical dysgenesis marked by a simplified gyral pattern, cortical atrophy, mild or focal cerebellar vermian volume loss, delayed myelination, progressive microcephaly, global growth and developmental delays, severe intellectual disabilities, and seizures refractory to treatment. {ECO:0000269|PubMed:24766809, ECO:0000269|PubMed:24766810}. Note=The disease is caused by mutations affecting the gene represented in this entry. Neurodegeneration is due to defects in tRNA splicing (PubMed:24766809, PubMed:24766810). {ECO:0000269|PubMed:24766809, ECO:0000269|PubMed:24766810}.;

Recessive Scores

pRec
0.142

Intolerance Scores

LoFtool
0.295
RVIS EVS
-0.05
RVIS percentile EVS
50.01

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.933

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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