PRKDC

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

Basic information

Region (hg38): 8:47773110-47960178

Previous symbols: [ "HYRC", "HYRC1" ]

Links

ENSG00000253729 ∙ NCBI:5591 ∙ OMIM:600899 ∙ HGNC:9413 ∙ Uniprot:P78527 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• severe combined immunodeficiency due to DNA-PKcs deficiency (Limited), mode of inheritance: AR
• severe combined immunodeficiency due to DNA-PKcs deficiency (Strong), mode of inheritance: AR
• severe combined immunodeficiency due to DNA-PKcs deficiency (Supportive), mode of inheritance: AR
• severe combined immunodeficiency due to DNA-PKcs deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 26 with or without neurologic abnormalities	AR	Allergy/Immunology/Infectious	Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; BMT has been reported	Allergy/Immunology/Infectious; Craniofacial; Neurologic	19075392; 23722905

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PRKDC gene.

• Severe combined immunodeficiency due to DNA-PKcs deficiency (2037 variants)
• Inborn genetic diseases (1896 variants)
• not provided (188 variants)
• not specified (59 variants)
• Microcephaly (2 variants)
• PRKDC-related condition (2 variants)
• Immunodeficiency 26 without neurologic abnormalities (1 variants)
• Malignant tumor of breast (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PRKDC gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			56	904	13	973
missense	1		2032	71	20	2124
nonsense			4			4
start loss						0
frameshift			3		2	5
inframe indel			8		1	9
splice donor/acceptor (+/-2bp)			7			7
splice region			72	91	10	173
non coding			66	265	71	402
Total	1	0	2176	1240	107

Variants in PRKDC

This is a list of pathogenic ClinVar variants found in the PRKDC region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
8-47774178-T-G		Severe combined immunodeficiency due to DNA-PKcs deficiency	Uncertain significance (Aug 17, 2023)
8-47774185-C-T		Severe combined immunodeficiency due to DNA-PKcs deficiency	Likely benign (Sep 19, 2023)
8-47774189-C-A		not specified	Uncertain significance (Nov 17, 2022)
8-47774195-T-G		Severe combined immunodeficiency due to DNA-PKcs deficiency	Uncertain significance (Jul 19, 2022)
8-47774197-C-G		not specified	Uncertain significance (Jul 08, 2021)
8-47774198-C-G		not specified	Uncertain significance (Oct 29, 2021)
8-47774203-T-A		not specified	Uncertain significance (Jul 13, 2021)
8-47774208-C-G		not specified	Uncertain significance (Nov 17, 2022)
8-47774210-A-T		not specified	Uncertain significance (Feb 19, 2023)
8-47774217-T-C		Severe combined immunodeficiency due to DNA-PKcs deficiency • not specified	Uncertain significance (Oct 13, 2023)
8-47774220-G-A		not specified	Uncertain significance (Jan 02, 2022)
8-47774227-T-C		not specified	Likely benign (Feb 15, 2022)
8-47774239-C-G		Severe combined immunodeficiency due to DNA-PKcs deficiency	Likely benign (Nov 19, 2022)
8-47774239-C-T			Likely benign (Oct 01, 2023)
8-47774247-T-G		not specified	Uncertain significance (Jan 16, 2023)
8-47774252-T-C		not specified	Uncertain significance (Jun 11, 2021)
8-47774259-C-G		Severe combined immunodeficiency due to DNA-PKcs deficiency	Uncertain significance (Oct 07, 2022)
8-47774268-G-T		Severe combined immunodeficiency due to DNA-PKcs deficiency	Uncertain significance (Dec 27, 2017)
8-47774277-C-G		Severe combined immunodeficiency due to DNA-PKcs deficiency	Uncertain significance (Jul 30, 2020)
8-47774280-G-A		Severe combined immunodeficiency due to DNA-PKcs deficiency	Uncertain significance (Feb 10, 2022)
8-47774281-T-G		Severe combined immunodeficiency due to DNA-PKcs deficiency	Uncertain significance (Jun 10, 2021)
8-47774298-T-C		not specified	Uncertain significance (Jul 26, 2021)
8-47774308-G-A		Severe combined immunodeficiency due to DNA-PKcs deficiency	Likely benign (Jan 24, 2023)
8-47774320-C-A		not specified	Likely benign (Feb 12, 2022)
8-47774330-T-C		Severe combined immunodeficiency due to DNA-PKcs deficiency	Uncertain significance (Jan 24, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PRKDC	protein_coding	protein_coding	ENST00000314191	87	187075

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.83e-29	1885	122762	9	124656	0.877

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.76	1727	2.08e+3	0.830	0.000115	26967
Missense in Polyphen		396	626.8	0.63178		8333
Synonymous	-1.09	835	796	1.05	0.0000463	7701
Loss of Function	12.8	5	201	0.0249	0.0000103	2670

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	2.00	1.82
Ashkenazi Jewish	1.00	0.906
East Asian	1.00	0.896
Finnish	1.00	0.913
European (Non-Finnish)	1.00	0.869
Middle Eastern	1.00	0.896
South Asian	1.00	0.895
Other	1.00	0.873

dbNSFP

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.
• Pathway: Cell cycle - Homo sapiens (human);Non-homologous end-joining - Homo sapiens (human);Cell Cycle;miRNA Regulation of DNA Damage Response;Retinoblastoma (RB) in Cancer;Fas Ligand (FasL) pathway and Stress induction of Heat Shock Proteins (HSP) regulation;Pathways Affected in Adenoid Cystic Carcinoma;ATM Signaling Network in Development and Disease;Non-homologous end joining;DNA Damage Response;DNA Repair;Nonhomologous End-Joining (NHEJ);DNA Double-Strand Break Repair;hiv-1 nef: negative effector of fas and tnf;Post-translational protein modification;STING mediated induction of host immune responses;Metabolism of proteins;Innate Immune System;Immune System;IRF3-mediated induction of type I IFN;fas signaling pathway (cd95);cell cycle: g2/m checkpoint;Coregulation of Androgen receptor activity;Protein ubiquitination;Cytosolic sensors of pathogen-associated DNA ;BARD1 signaling events;E3 ubiquitin ligases ubiquitinate target proteins;Class I PI3K signaling events mediated by Akt;DNA-PK pathway in nonhomologous end joining (Consensus)

Recessive Scores

• pRec: 0.665

Haploinsufficiency Scores

• pHI: 0.746
• hipred: Y
• hipred_score: 0.758
• ghis: 0.639

Essentials

• essential_gene_CRISPR2: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.921

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Prkdc
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; muscle phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; skeleton phenotype; renal/urinary system phenotype; no phenotypic analysis (no description of morphological, physiological or behavioral information presented); immune system phenotype; vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; digestive/alimentary phenotype; neoplasm; pigmentation phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: prkdc
• Affected structure: neutrophil
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: telomere maintenance;somitogenesis;negative regulation of protein phosphorylation;activation of innate immune response;B cell lineage commitment;pro-B cell differentiation;T cell lineage commitment;negative regulation of immunoglobulin production;double-strand break repair;double-strand break repair via nonhomologous end joining;cellular protein modification process;protein phosphorylation;cellular response to DNA damage stimulus;brain development;heart development;cell population proliferation;intrinsic apoptotic signaling pathway in response to DNA damage;response to gamma radiation;response to activity;telomere capping;protein ubiquitination;peptidyl-serine phosphorylation;protein destabilization;positive regulation of type I interferon production;cellular response to insulin stimulus;T cell differentiation in thymus;immunoglobulin V(D)J recombination;T cell receptor V(D)J recombination;ectopic germ cell programmed cell death;regulation of circadian rhythm;positive regulation of apoptotic process;negative regulation of apoptotic process;innate immune response;positive regulation of transcription by RNA polymerase II;positive regulation of fibroblast proliferation;rhythmic process;spleen development;thymus development;positive regulation of developmental growth;regulation of smooth muscle cell proliferation;signal transduction involved in mitotic G1 DNA damage checkpoint;double-strand break repair via alternative nonhomologous end joining;negative regulation of cellular senescence;negative regulation of response to gamma radiation
• Cellular component: nuclear chromosome, telomeric region;nucleus;nucleoplasm;transcription factor complex;nucleolus;cytosol;DNA-dependent protein kinase-DNA ligase 4 complex;membrane;protein-containing complex;protein-DNA complex;nonhomologous end joining complex
• Molecular function: double-stranded DNA binding;RNA binding;protein kinase activity;protein serine/threonine kinase activity;DNA-dependent protein kinase activity;protein binding;ATP binding;transcription factor binding;enzyme binding;protein domain specific binding