PNKP

protein-coding

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

Gene summary

This locus represents a gene involved in DNA repair. In response to ionizing radiation or oxidative damage, the protein encoded by this locus catalyzes 5' phosphorylation and 3' dephosphorylation of nucleic acids. Mutations at this locus have been associated with microcephaly, seizures, and developmental delay.[provided by RefSeq, Sep 2010]

MANE transcript

NM_007254.4

Inheritance

AR, AD

ClinVar variants

P:161U:427B:284

Top phenotype

Ataxia-oculomotor apraxia 4; Charcot-Marie-Tooth disease, type 2B2; Microcephaly, seizures, and developmental delay

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr19:49,859,882-49,878,351

External References & Databases

Ensembl (ENSG00000039650)

Transcript & Mutation Effects

hg38 • Region Span ~18.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease type 2B2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011570

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease type 2B2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011570

Submitter: Orphanet

microcephaly, seizures, and developmental delaySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013254

Submitter: PanelApp Australia

ataxia - oculomotor apraxia type 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014557

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

microcephaly, seizures, and developmental delaySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013254

Submitter: Labcorp Genetics (formerly Invitae)

microcephaly, seizures, and developmental delaySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013254

Submitter: Ambry Genetics

ataxia - oculomotor apraxia type 4SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014557

Submitter: Orphanet

Charcot-Marie-Tooth disease type 2B2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011570

Submitter: Labcorp Genetics (formerly Invitae)

ataxia - oculomotor apraxia type 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014557

Submitter: G2P

microcephaly, seizures, and developmental delayDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013254

Submitter: ClinGen

PNKP was first reported in relation to autosomal recessive Microcephaly, seizures, and developmental delay in 2010 (Shen et al., 2010). At least 34 variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 11 unrelated probands with Microcephaly, seizures, and developmental delay in 4 publications (20118933, 23224214, 29243230, 25728773). Variants in this gene segregated with disease in 7 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function (Shen et al., 2010) Of note, this gene has also been implicated in autosomal recessive Ataxia-oculomotor apraxia. In particular c.1253_1269dup17 is associated with both conditions. This condition will be assessed separately. This gene-disease association is supported by in vitro functional assays (McKinnon and Caldecott, 2007; Mani et al, 2010; Reynolds et al, 2010). In summary, PNKP is definitively associated with autosomal recessive Microcephaly, seizures, and developmental delay. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

genetic developmental and epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Orphanet

ataxia - oculomotor apraxia type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014557

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Ataxia-oculomotor apraxia 4; Charcot-Marie-Tooth disease, type 2B2; Microcephaly, seizures, and developmental delayAR

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

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 20118933; 23224214; 25728773; 27066567; 30039206

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PNKP variants in ClinVar

19 Conditions Cataloged

Developmental and epileptic encephalopathy, 12Total: 963

not providedTotal: 385

Inborn genetic diseasesTotal: 190

not specifiedTotal: 150

Microcephaly, seizures, and developmental delayTotal: 120

Ataxia - oculomotor apraxia type 4Total: 46

PNKP-related disorderTotal: 37

Charcot-Marie-Tooth disease type 2B2Total: 24

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007254.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	13 clinvar	257 clinvar	6 clinvar	277
missense	5 clinvar	9 clinvar	408 clinvar	19 clinvar	1 clinvar	442
nonsense	13 clinvar	13 clinvar	1 clinvar			27
start loss						0
frameshift	49 clinvar	31 clinvar	3 clinvar			83
splice donor/acceptor (+/-2bp)	13 clinvar	27 clinvar	2 clinvar	1 clinvar		43
Total	80	81	427	277	7	872

Highest pathogenic variant AF is 0.0017782227

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 73 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007254.4	RefSeq	NP_009185.2	16	MANE Select
ENST00000322344.8	Ensembl	ENSP00000323511.2	16	MANE Select
ENST00000593946.5	Ensembl	ENSP00000468896.1	2	Standard
ENST00000596014.5	Ensembl	ENSP00000472300.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

nucleotide-excision repair, DNA damage removal
DNA-dependent DNA replication
DNA repair
response to oxidative stress
response to radiation

Molecular Function

damaged DNA binding
double-stranded DNA binding
endonuclease activity
protein binding
ATP binding

Cellular Component

nucleus
nucleoplasm
nucleolus
mitochondrion
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000322344
Coding exons: 16
Length: 6706
Individuals with no LoFs: 125676
Homozygous LoFs: 0
Heterozygous LoFs: 72
Defined: 125748
p: 0.000286

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.31	383	317	1.21	0.0000226	3279
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00039	0.00037	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00034	0.00033	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00029	0.00028	rare
South Asian	0.00037	0.00036	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.182

Intolerance Scores

LoFtool: 0.701
RVIS EVS: -0.53
RVIS percentile EVS: 20.86

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.995

Gene Damage Prediction

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