PNKP

polynucleotide kinase 3'-phosphatase, the group of HAD Asp-based non-protein phosphatases

Basic information

Region (hg38): 19:49859881-49878351

Links

ENSG00000039650 ∙ NCBI:11284 ∙ OMIM:605610 ∙ HGNC:9154 ∙ Uniprot:Q96T60 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• ataxia - oculomotor apraxia type 4 (Definitive), mode of inheritance: AR
• microcephaly, seizures, and developmental delay (Strong), mode of inheritance: AR
• ataxia - oculomotor apraxia type 4 (Definitive), mode of inheritance: AR
• developmental and epileptic encephalopathy (Supportive), mode of inheritance: AD
• Charcot-Marie-Tooth disease type 2B2 (Supportive), mode of inheritance: AR
• ataxia - oculomotor apraxia type 4 (Supportive), mode of inheritance: AR
• Charcot-Marie-Tooth disease type 2B2 (Strong), mode of inheritance: AR
• microcephaly, seizures, and developmental delay (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ataxia-oculomotor apraxia 4; Charcot-Marie-Tooth disease, type 2B2; Microcephaly, seizures, and developmental delay	AR	General	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	Neurologic	20118933; 23224214; 25728773; 27066567; 30039206
As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

ClinVar

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

• Developmental and epileptic encephalopathy, 12 (797 variants)
• not provided (329 variants)
• not specified (139 variants)
• Inborn genetic diseases (133 variants)
• Microcephaly, seizures, and developmental delay (100 variants)
• Ataxia - oculomotor apraxia type 4 (14 variants)
• Charcot-Marie-Tooth disease type 2B2;Microcephaly, seizures, and developmental delay;Ataxia - oculomotor apraxia type 4 (8 variants)
• Microcephaly, seizures, and developmental delay;Ataxia - oculomotor apraxia type 4 (7 variants)
• Charcot-Marie-Tooth disease type 2B2 (5 variants)
• Ataxia - oculomotor apraxia type 4;Microcephaly, seizures, and developmental delay (4 variants)
• Abnormality of the nervous system (3 variants)
• Abnormal cerebral morphology (2 variants)
• Microcephaly, seizures, and developmental delay;Ataxia - oculomotor apraxia type 4;Charcot-Marie-Tooth disease type 2B2 (2 variants)
• Seizure (2 variants)
• Charcot-Marie-Tooth disease type 2B2;Ataxia - oculomotor apraxia type 4;Microcephaly, seizures, and developmental delay (2 variants)
• PNKP-related condition (2 variants)
• Epileptic encephalopathy (1 variants)
• Pyridoxine-dependent epilepsy (1 variants)
• PNKP-related disorders (1 variants)
• Intellectual disability (1 variants)
• Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PNKP 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			11	165	2	178
missense	2	2	355	5		364
nonsense	11	8	1			20
start loss						0
frameshift	31	18	2			51
inframe indel		1	15			16
splice donor/acceptor (+/-2bp)	6	15	1			22
splice region	2	3	41	43	4	93
non coding	1	1	13	171	18	204
Total	51	45	398	341	20

Highest pathogenic variant AF is 0.000185

Variants in PNKP

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

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

Position	Type	Phenotype	Significance	ClinVar
19-49859993-G-A		not specified	Uncertain significance (Dec 19, 2022)
19-49860080-T-G		not specified	Uncertain significance (Dec 08, 2021)
19-49860115-C-T		not specified	Uncertain significance (Mar 23, 2022)
19-49860119-G-A		not specified	Uncertain significance (Jun 03, 2022)
19-49860137-A-G		not specified	Uncertain significance (Sep 29, 2023)
19-49861087-G-GC			Likely benign (Jun 14, 2018)
19-49861166-T-C			Likely benign (Jun 19, 2018)
19-49861205-C-T		Microcephaly, seizures, and developmental delay	Uncertain significance (Jan 13, 2018)
19-49861225-T-G		Microcephaly, seizures, and developmental delay	Uncertain significance (Jan 13, 2018)
19-49861227-T-G		Microcephaly, seizures, and developmental delay	Benign (Jan 12, 2018)
19-49861231-G-A		not specified	Likely benign (Sep 21, 2016)
19-49861233-G-A		not specified • Microcephaly, seizures, and developmental delay • Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 12, 2018)
19-49861243-G-C			Likely benign (Oct 24, 2017)
19-49861248-T-C		Developmental and epileptic encephalopathy, 12	Uncertain significance (Jan 13, 2022)
19-49861249-C-T		Developmental and epileptic encephalopathy, 12	Likely benign (Oct 13, 2022)
19-49861253-C-T		Developmental and epileptic encephalopathy, 12	Uncertain significance (Aug 16, 2022)
19-49861254-C-T		Developmental and epileptic encephalopathy, 12	Likely benign (Jan 03, 2024)
19-49861255-T-C		Ataxia - oculomotor apraxia type 4;Microcephaly, seizures, and developmental delay • Microcephaly, seizures, and developmental delay • Developmental and epileptic encephalopathy, 12	Uncertain significance (Aug 27, 2021)
19-49861256-C-G		Seizure • Developmental and epileptic encephalopathy, 12	Uncertain significance (Jan 27, 2022)
19-49861256-C-T		Developmental and epileptic encephalopathy, 12	Uncertain significance (Jun 04, 2022)
19-49861257-G-A		not specified • Developmental and epileptic encephalopathy, 12 • Microcephaly, seizures, and developmental delay • Inborn genetic diseases	Benign (Jan 22, 2024)
19-49861257-G-C		Developmental and epileptic encephalopathy, 12	Likely benign (Feb 14, 2023)
19-49861258-G-C			Uncertain significance (Dec 29, 2016)
19-49861260-G-A		Developmental and epileptic encephalopathy, 12 • PNKP-related disorder	Likely benign (Sep 10, 2023)
19-49861261-A-T		Developmental and epileptic encephalopathy, 12	Uncertain significance (Mar 13, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PNKP	protein_coding	protein_coding	ENST00000322344	16	6706

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.66e-14	0.0817	125676	0	72	125748	0.000286

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.31	383	317	1.21	0.0000226	3279
Missense in Polyphen		130	110.87	1.1726		1191
Synonymous	-4.53	206	138	1.49	0.0000106	1081
Loss of Function	0.704	23	26.9	0.854	0.00000134	311

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000658	0.000633
Ashkenazi Jewish	0.00	0.00
East Asian	0.000344	0.000326
Finnish	0.000234	0.000231
European (Non-Finnish)	0.000291	0.000281
Middle Eastern	0.000344	0.000326
South Asian	0.000365	0.000359
Other	0.000489	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways. Through its two catalytic activities, PNK ensures that DNA termini are compatible with extension and ligation by either removing 3'-phosphates from, or by phosphorylating 5'-hydroxyl groups on, the ribose sugar of the DNA backbone. {ECO:0000269|PubMed:10446192}.
• Disease: DISEASE: Microcephaly, seizures, and developmental delay (MCSZ) [MIM:613402]: A disease characterized by infantile-onset seizures, microcephaly, severe intellectual disability and delayed motor milestones with absent speech or only achieving a few words. Most patients also have behavioral problems with hyperactivity. Microcephaly is progressive and without neuronal migration or structural abnormalities, consistent with primary microcephaly. {ECO:0000269|PubMed:20118933, ECO:0000269|PubMed:27232581}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ataxia-oculomotor apraxia 4 (AOA4) [MIM:616267]: An autosomal recessive disease characterized by cerebellar ataxia, oculomotor apraxia, areflexia and peripheral neuropathy. {ECO:0000269|PubMed:25728773}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: DNA Repair;Resolution of Abasic Sites (AP sites);Base Excision Repair;APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway;DNA-PK pathway in nonhomologous end joining (Consensus)

Recessive Scores

• pRec: 0.182

Intolerance Scores

• loftool: 0.701
• rvis_EVS: -0.53
• rvis_percentile_EVS: 20.86

Haploinsufficiency Scores

• pHI: 0.341
• hipred: Y
• hipred_score: 0.575
• ghis: 0.534

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.995

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pnkp
• 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); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); 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); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: nucleotide-excision repair, DNA damage removal;DNA-dependent DNA replication;DNA repair;response to oxidative stress;response to radiation;negative regulation of protein ADP-ribosylation;dephosphorylation;positive regulation of telomere maintenance via telomerase;DNA damage response, detection of DNA damage;nucleotide phosphorylation;nucleoside monophosphate phosphorylation;positive regulation of telomerase activity;nucleic acid phosphodiester bond hydrolysis;DNA 3' dephosphorylation involved in DNA repair;polynucleotide 3' dephosphorylation;positive regulation of telomere capping
• Cellular component: nucleus;nucleoplasm;nucleolus;mitochondrion;membrane
• Molecular function: damaged DNA binding;double-stranded DNA binding;endonuclease activity;protein binding;ATP binding;purine nucleotide binding;polynucleotide 3'-phosphatase activity;ATP-dependent polydeoxyribonucleotide 5'-hydroxyl-kinase activity;nucleoside monophosphate kinase activity