GeneBe

PRKDC

protein-coding

protein kinase, DNA-activated, catalytic subunit, the group of Armadillo like helical domain containing

Gene summary

This gene encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK). It functions with the Ku70/Ku80 heterodimer protein in DNA double strand break repair and recombination. The protein encoded is a member of the PI3/PI4-kinase family.[provided by RefSeq, Jul 2010]

Previous symbols:
  • HYRC
  • HYRC1

MANE transcript

NM_006904.7

Inheritance

AR

ClinVar variants

P:4U:2651B:1587

Top phenotype

Immunodeficiency 26 with or without neurologic abnormalities

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr8:47,773,111-47,960,178

External References & Databases

Ensembl (ENSG00000253729)NCBI Gene (5591)OMIM (600899)HGNC:9413GenCCUniProt (P78527)AlphaFoldClinVar (PRKDC)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~187.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

severe combined immunodeficiency due to DNA-PKcs deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014423

Submitter: Orphanet

severe combined immunodeficiency due to DNA-PKcs deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014423

Submitter: PanelApp Australia

severe combined immunodeficiency due to DNA-PKcs deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014423

Submitter: Labcorp Genetics (formerly Invitae)

severe combined immunodeficiency due to DNA-PKcs deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014423

Submitter: Ambry Genetics

severe combined immunodeficiency due to DNA-PKcs deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014423

Submitter: ClinGen

PRKDC was first reported in relation to autosomal recessive combined immunodeficiency due to DNA-PKcs deficiency in 2009 (van der Burg et al., PMID: 1907532). The phenotype of patients with DNA-PKcs deficiency can be variable but may include: a spectrum of combined immunodeficiency, recurrent infections, progressive pulmonary disease, growth retardation, dysmorphic facies, neurologic abnormalities, and autoimmunity. PRKDC encodes the catalytic subunit of a nuclear DNA-dependent serine/threonine protein kinase (DNA-PK) which is involved in NHEJ during DNA double-strand break (DSB) repair and for V(D)J recombination during immune development. Patients with hypomorphic mutations, with partially preserved T and B cell development, can present with signs of autoimmunity owing to the role of DNA-PKcs in regulating expression of AutoImmune-Regulator (AIRE)-dependent peripheral tissue antigens during thymocyte selection. It is a rare inborn error of immunity. Thus far, pathogenic missense variations and splicing abnormalities have been reported in several publications (PMIDs: 19075392, 23722905, 30121298, 25842288, 26546606, 26122175, 30778343, 29921932) and many are included in this curation. Nonsense or frameshift variants have not yet been described in humans. The mechanism of pathogenicity is reported to be hypomorphic loss of function. Heterozygous carriers have not been shown to have a clinical phenotype. This gene-disease association is also supported by accompanying experimental evidence in both PRKDC-deficient patients (PMIDs 19075392, 23722905, 26546606). and animal models (PMIDs 8524788, 11489998, 22981234, 27566103). In summary, PRKDC is definitively associated with autosomal recessive combined immunodeficiency due to DNA-PKcs deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on November 18, 2021 (SOP Version 8).

Clinical Genomic Database (CGD)

Immunodeficiency 26 with or without neurologic abnormalitiesAR

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; BMT has been reported

Refs: 19075392; 23722905Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PRKDC variants in ClinVar

8 Conditions Cataloged
Severe combined immunodeficiency due to DNA-PKcs deficiencyTotal: 2706
not specifiedTotal: 2678
not providedTotal: 210
PRKDC-related disorderTotal: 45
MicrocephalyTotal: 4
IMMUNODEFICIENCY 26 WITHOUT NEUROLOGIC ABNORMALITIESTotal: 1
Malignant tumor of breastTotal: 1
See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006904.7. 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
21
clinvar
1430
clinvar
15
clinvar
 1466
missense
2
clinvar
1
clinvar
2593
clinvar
126
clinvar
14
clinvar
 2736
nonsense
6
clinvar
 6
start loss
0
frameshift
1
clinvar
5
clinvar
2
clinvar
 8
splice donor/acceptor (+/-2bp)
26
clinvar
 26
Total2226511556314242

Highest pathogenic variant AF is 0.000010267137

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006904.7RefSeqNP_008835.586MANE Select
ENST00000314191.7EnsemblENSP00000313420.386MANE Select
NM_001081640.2RefSeqNP_001075109.185Standard
ENST00000338368.7EnsemblENSP00000345182.485Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
prkdcDanio rerio

Structure: neutrophil

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cell cycle - Homo sapiens (human)
  • Non-homologous end-joining - Homo sapiens (human)
  • Cell Cycle
  • miRNA Regulation of DNA Damage Response
  • Retinoblastoma (RB) in Cancer

Biological Process

  • telomere maintenance
  • somitogenesis
  • negative regulation of protein phosphorylation
  • activation of innate immune response
  • B cell lineage commitment

Molecular Function

  • double-stranded DNA binding
  • RNA binding
  • protein kinase activity
  • protein serine/threonine kinase activity
  • DNA-dependent protein kinase activity

Cellular Component

  • nuclear chromosome, telomeric region
  • nucleus
  • nucleoplasm
  • transcription factor complex
  • nucleolus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000314191
Coding exons
87
Length
187075
Individuals with no LoFs
1885
Homozygous LoFs
122762
Heterozygous LoFs
9
Defined
124656
p
0.877
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.7617272.08e+30.8300.00011526967
Missense (PolyPhen)396626.80.631788333
Synonymous-1.098357961.050.00004637701
Loss of Function12.852010.02490.00001032670

Population LoF Frequency

PopulationCAFp-valueStatus
African1.00.82notable
Latino/Admixed American1.00.89notable
Ashkenazi Jewish1.00.91notable
East Asian1.00.90notable
Finnish1.00.91notable
European (Non-Finnish)1.00.87notable
South Asian1.00.89notable
Other1.00.87notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. Must be bound to DNA to express its catalytic properties. Promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C). The assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step. Required to protect and align broken ends of DNA. May also act as a scaffold protein to aid the localization of DNA repair proteins to the site of damage. Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion. Also involved in modulation of transcription. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX, thereby regulating DNA damage response mechanism. Phosphorylates DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, SRF, XRCC1, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC and RFA2. Can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA. Ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D. Contributes to the determination of the circadian period length by antagonizing phosphorylation of CRY1 'Ser-588' and increasing CRY1 protein stability, most likely through an indirect mechanism. Interacts with CRY1 and CRY2; negatively regulates CRY1 phosphorylation. Plays a role in the regulation of DNA virus- mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway. {ECO:0000269|PubMed:12649176, ECO:0000269|PubMed:14734805, ECO:0000269|PubMed:15574326, ECO:0000269|PubMed:28712728, ECO:0000269|PubMed:9679063}.;
Disease
DISEASE: Immunodeficiency 26 with or without neurologic abnormalities (IMD26) [MIM:615966]: A form of severe combined immunodeficiency characterized by reduced or absent T and B cells, recurrent candidiasis, and lower respiratory tract infections. Some patients show dysmorphic features, severe growth failure, microcephaly, seizures, and impaired neurological functions. {ECO:0000269|PubMed:19075392, ECO:0000269|PubMed:23722905}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.665

Essentials

Essential (CRISPR2)
E
Indispensability pred.
E
Indispensability score
0.921

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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