GeneBe

VRK1

protein-coding

VRK serine/threonine kinase 1

Gene summary

This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. This gene is widely expressed in human tissues and has increased expression in actively dividing cells, such as those in testis, thymus, fetal liver, and carcinomas. Its protein localizes to the nucleus and has been shown to promote the stability and nuclear accumulation of a transcriptionally active p53 molecule and, in vitro, to phosphorylate Thr18 of p53 and reduce p53 ubiquitination. This gene, therefore, may regulate cell proliferation. This protein also phosphorylates histone, casein, and the transcription factors ATF2 (activating transcription factor 2) and c-JUN. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003384.3

Inheritance

AR

ClinVar variants

P:102U:160B:137

Top phenotype

Pontocerebellar hypoplasia type 1A; Neuronopathy, distal hereditary motor, autosomal recessive 10

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr14:96,797,304-96,954,846

External References & Databases

Ensembl (ENSG00000100749)NCBI Gene (7443)OMIM (602168)HGNC:12718GenCCUniProt (Q99986)AlphaFoldClinVar (VRK1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~157.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pontocerebellar hypoplasia type 1ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011866

Submitter: PanelApp Australia

pontocerebellar hypoplasia type 1AMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011866

Submitter: Ambry Genetics

neuronopathy, distal hereditary motor, autosomal recessive 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0957876

Submitter: PanelApp Australia

pontocerebellar hypoplasia type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016396

Submitter: Orphanet

pontocerebellar hypoplasia type 1ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011866

Submitter: Labcorp Genetics (formerly Invitae)

microcephaly-complex motor and sensory axonal neuropathy syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018507

Submitter: Orphanet

pontocerebellar hypoplasia type 1ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011866

Submitter: G2P

pontocerebellar hypoplasia type 1ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011866

Submitter: Natera

pontocerebellar hypoplasia type 1ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011866

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Pontocerebellar hypoplasia type 1A; Neuronopathy, distal hereditary motor, autosomal recessive 10AR

Manifestation: 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: 19646678; 21937992; 24126608; 30847374; 31090908; 31837156; 35641352; 37257665Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VRK1 variants in ClinVar

19 Conditions Cataloged
Pontocerebellar hypoplasia type 1ATotal: 497
Inborn genetic diseasesTotal: 73
not providedTotal: 69
Neuronopathy, distal hereditary motor, autosomal recessive 10Total: 29
Congenital pontocerebellar hypoplasia type 1Total: 28
not specifiedTotal: 25
Distal spinal muscular atrophyTotal: 7
VRK1-related disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003384.3. 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
6
clinvar
133
clinvar
 139
missense
1
clinvar
12
clinvar
149
clinvar
4
clinvar
 166
nonsense
13
clinvar
8
clinvar
 21
start loss
1
clinvar
 1
frameshift
22
clinvar
25
clinvar
2
clinvar
 49
splice donor/acceptor (+/-2bp)
2
clinvar
19
clinvar
2
clinvar
 23
Total38641601370399

Highest pathogenic variant AF is 0.000047914946

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 125 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003384.3RefSeqNP_003375.112MANE Select
ENST00000216639.8EnsemblENSP00000216639.312MANE Select
NM_001411051.1RefSeqNP_001397980.113Standard
NM_001411053.1RefSeqNP_001397982.112Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Clearance of Nuclear Envelope Membranes from Chromatin
  • Nuclear Envelope Breakdown
  • Mitotic Prophase
  • Initiation of Nuclear Envelope Reformation
  • Nuclear Envelope Reassembly

Biological Process

  • protein phosphorylation
  • mitotic nuclear envelope disassembly
  • mitotic nuclear envelope reassembly
  • peptidyl-serine phosphorylation
  • peptidyl-threonine phosphorylation

Molecular Function

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

Cellular Component

  • nucleus
  • nucleoplasm
  • nucleolus
  • cytoplasm
  • Golgi stack

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000216639
Coding exons
12
Length
134419
Individuals with no LoFs
125710
Homozygous LoFs
0
Heterozygous LoFs
36
Defined
125746
p
0.000143
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.171672150.7760.00001132603
Missense (PolyPhen)3058.0090.51716678
Synonymous0.5706166.90.9110.00000330688
Loss of Function2.94924.80.3630.00000133308

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.0000870.000087rare
Ashkenazi Jewish0.00160.0016notable
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000980.000097rare
South Asian0.0000330.000033rare
Other0.000360.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Serine/threonine kinase involved in Golgi disassembly during the cell cycle: following phosphorylation by PLK3 during mitosis, required to induce Golgi fragmentation. Acts by mediating phosphorylation of downstream target protein. Phosphorylates 'Thr- 18' of p53/TP53 and may thereby prevent the interaction between p53/TP53 and MDM2. Phosphorylates casein and histone H3. Phosphorylates BANF1: disrupts its ability to bind DNA, reduces its binding to LEM domain-containing proteins and causes its relocalization from the nucleus to the cytoplasm. Phosphorylates ATF2 which activates its transcriptional activity. {ECO:0000269|PubMed:10951572, ECO:0000269|PubMed:14645249, ECO:0000269|PubMed:15105425, ECO:0000269|PubMed:16495336, ECO:0000269|PubMed:18617507, ECO:0000269|PubMed:19103756}.;
Disease
DISEASE: Pontocerebellar hypoplasia 1A (PCH1A) [MIM:607596]: A disorder characterized by an abnormally small cerebellum and brainstem, central and peripheral motor dysfunction from birth, gliosis and spinal cord anterior horn cells degeneration resembling infantile spinal muscular atrophy. Additional features include muscle hypotonia, congenital contractures and respiratory insufficiency that is evident at birth. {ECO:0000269|PubMed:19646678}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.103

Intolerance Scores

LoFtool
0.848
RVIS EVS
-0.38
RVIS percentile EVS
27.69

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
E
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.966

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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