PENK

protein-coding

proenkephalin, the group of Neuropeptides

Gene summary

This gene encodes a preproprotein that is proteolytically processed to generate multiple protein products. These products include the pentapeptide opioids Met-enkephalin and Leu-enkephalin, which are stored in synaptic vesicles, then released into the synapse where they bind to mu- and delta-opioid receptors to modulate the perception of pain. Other non-opioid cleavage products may function in distinct biological activities. [provided by RefSeq, Jul 2015]

MANE transcript

NM_001135690.3

Inheritance

—

ClinVar variants

U:36B:10

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr8:56,436,674-56,446,671

External References & Databases

Ensembl (ENSG00000181195)

Transcript & Mutation Effects

hg38 • Region Span ~10.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PENK variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 38

not providedTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001135690.3. 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				2 clinvar	4 clinvar	6
missense			36 clinvar	3 clinvar	1 clinvar	40
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	36	5	5	46

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001135690.3	RefSeq	NP_001129162.1	2	MANE Select
ENST00000451791.7	Ensembl	ENSP00000400894.2	2	MANE Select
ENST00000314922.3	Ensembl	ENSP00000324248.3	2	Standard
ENST00000314922.4	Ensembl	ENSP00000324248.3	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling by GPCR
Signal Transduction
Post-translational protein phosphorylation
Post-translational protein modification
Metabolism of proteins

Biological Process

osteoblast differentiation
behavioral fear response
response to hypoxia
startle response
aggressive behavior

Molecular Function

opioid peptide activity
neuropeptide hormone activity
opioid receptor binding

Cellular Component

extracellular region
endoplasmic reticulum lumen
plasma membrane
dendrite
symmetric synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000314922
Coding exons: 2
Length: 10061
Individuals with no LoFs: 125653
Homozygous LoFs: 0
Heterozygous LoFs: 95
Defined: 125748
p: 0.000378

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.725	179	154	1.16	0.00000853	1756
Missense (PolyPhen)		57	50.235	1.1347		558
Synonymous	0.400	58	62.0	0.935	0.00000346	498
Loss of Function	1.01	7	10.5	0.665	6.25e-7	123

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00098	0.00098	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.0022	0.0022	notable
East Asian	0.00022	0.00022	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.00029	0.00029	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Met- and Leu-enkephalins compete with and mimic the effects of opiate drugs. They play a role in a number of physiologic functions, including pain perception and responses to stress. PENK(114-133) and PENK(237-258) increase glutamate release in the striatum. PENK(114-133) decreases GABA concentration in the striatum.;

Recessive Scores

pRec: 0.375

Intolerance Scores

LoFtool: 0.826
RVIS EVS: 0.31
RVIS percentile EVS: 72.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.506

Gene Damage Prediction

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