PCSK2
protein-codingproprotein convertase subtilisin/kexin type 2, the group of Proprotein convertase subtilisin/kexin family
Gene summary
This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The protein undergoes an initial autocatalytic processing event and interacts with a neuroendocrine secretory protein in the ER, exits the ER and sorts to secretory granules, where it is cleaved and catalytically activated during intracellular transport. The encoded protease is packaged into and activated in dense core secretory granules and expressed in the neuroendocrine system and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It functions in the proteolytic activation of polypeptide hormones and neuropeptides precursors. Single nucleotide polymorphisms in this gene may increase susceptibility to myocardial infarction and type 2 diabetes. This gene may also play a role in tumor development and progression. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2014]
- NEC2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~258.5 kbGenCC 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 PCSK2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002594.5. 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 | 1 | 1 | ||||
| missense | 45 | 1 | 46 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 0 | 49 | 1 | 1 | 51 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002585.2 | 12 | MANE Select | |
| Ensembl | ENSP00000262545.2 | 12 | MANE Select | |
| RefSeq | NP_001188457.1 | 12 | Standard | |
| RefSeq | NP_001188458.1 | 11 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Levomethadyl Acetate Action Action Pathway
- Fluoxetine Action Pathway
- Citalopram Action Pathway
- Escitalopram Action Pathway
- Imipramine Action Pathway
Biological Process
- proteolysis
- nervous system development
- protein processing
- peptide hormone processing
- protein autoprocessing
Molecular Function
- serine-type endopeptidase activity
- protein binding
- protein-containing complex binding
Cellular Component
- extracellular space
- nucleus
- membrane
- transport vesicle
- secretory granule
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000262545
- Coding exons
- 12
- Length
- 258472
- Individuals with no LoFs
- 125742
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125746
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.55 | 199 | 398 | 0.500 | 0.0000235 | 4215 |
| Missense (PolyPhen) | 56 | 199.31 | 0.28097 | 2043 | ||
| Synonymous | -0.301 | 167 | 162 | 1.03 | 0.0000112 | 1240 |
| Loss of Function | 4.77 | 3 | 32.2 | 0.0931 | 0.00000172 | 333 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000026 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. Responsible for the release of glucagon from proglucagon in pancreatic A cells. {ECO:0000269|PubMed:28719828, ECO:0000269|PubMed:9287128}.;
Recessive Scores
- pRec
- 0.268
Intolerance Scores
- LoFtool
- 0.158
- RVIS EVS
- -1.11
- RVIS percentile EVS
- 6.72
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.534
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |