PNKD

protein-coding

PNKD metallo-beta-lactamase domain containing, the group of MicroRNA protein coding host genes|MBL domain containing glyoxalase 2 subfamily|Mitochondrial respiratory chain complex assembly factors

Gene summary

This gene is thought to play a role in the regulation of myofibrillogenesis. Mutations in this gene have been associated with the movement disorder paroxysmal non-kinesigenic dyskinesia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

MANE transcript

NM_015488.5

Inheritance

ClinVar variants

P:3U:341B:129

Top phenotype

paroxysmal nonkinesigenic dyskinesia 1

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr2:218,269,651-218,346,793

External References & Databases

Ensembl (ENSG00000127838)

Transcript & Mutation Effects

hg38 • Region Span ~77.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Tourette syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007661

Submitter: Labcorp Genetics (formerly Invitae)

paroxysmal nonkinesigenic dyskinesia 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007326

Submitter: Genomics England PanelApp

paroxysmal nonkinesigenic dyskinesia 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700089

Submitter: PanelApp Australia

paroxysmal nonkinesigenic dyskinesia 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007326

Submitter: Orphanet

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PNKD variants in ClinVar

11 Conditions Cataloged

Paroxysmal nonkinesigenic dyskinesiaTotal: 511

not providedTotal: 102

not specifiedTotal: 72

Paroxysmal nonkinesigenic dyskinesia 1Total: 56

Inborn genetic diseasesTotal: 56

PNKD-related disorderTotal: 18

Episodic hemiplegiaTotal: 1

Paroxysmal dystoniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015488.5. 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			7 clinvar	93 clinvar	5 clinvar	105
missense		3 clinvar	282 clinvar	29 clinvar	1 clinvar	315
nonsense			15 clinvar			15
start loss			2 clinvar			2
frameshift			20 clinvar	1 clinvar		21
splice donor/acceptor (+/-2bp)			15 clinvar			15
Total	0	3	341	123	6	473

Highest pathogenic variant AF is 0.000022309063

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015488.5	RefSeq	NP_056303.3	10	MANE Select
ENST00000273077.9	Ensembl	ENSP00000273077.4	10	MANE Select
NM_001077399.3	RefSeq	NP_001070867.1	3	Standard
NM_022572.4	RefSeq	NP_072094.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

methylglyoxal catabolic process to D-lactate via S-lactoyl-glutathione
regulation of synaptic transmission, dopaminergic
regulation of dopamine metabolic process
negative regulation of neurotransmitter secretion
neuromuscular process controlling posture

Molecular Function

hydroxyacylglutathione hydrolase activity
protein binding
metal ion binding

Cellular Component

nucleus
mitochondrion
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000273077
Coding exons: 10
Length: 76402
Individuals with no LoFs: 125681
Homozygous LoFs: 0
Heterozygous LoFs: 67
Defined: 125748
p: 0.000266

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.323	215	229	0.940	0.0000145	2413
Missense (PolyPhen)		56	64.772	0.86457		684
Synonymous	1.08	80	93.3	0.857	0.00000527	823
Loss of Function	1.11	14	19.2	0.728	9.19e-7	219

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00039	0.00035	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00044	0.00040	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable hydrolase that plays an aggravative role in the development of cardiac hypertrophy via activation of the NF-kappa- B signaling pathway. {ECO:0000250}.;
Disease: DISEASE: Dystonia 8 (DYT8) [MIM:118800]: A paroxysmal non- kinesigenic dystonia/dyskinesia. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. Dystonia type 8 is characterized by attacks of involuntary movements brought on by stress, alcohol, fatigue or caffeine. The attacks generally last between a few seconds and four hours or longer. The attacks may begin in one limb and spread throughout the body, including the face. {ECO:0000269|PubMed:15262732, ECO:0000269|PubMed:15824259, ECO:0000269|PubMed:16632198, ECO:0000269|PubMed:16717228, ECO:0000269|PubMed:16972263}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.258

Intolerance Scores

LoFtool: 0.156
RVIS EVS: -0.36
RVIS percentile EVS: 29.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

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