PCSK6
protein-codingproprotein convertase subtilisin/kexin type 6, 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 encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. The encoded protease is constitutively secreted into the extracellular matrix and expressed in many tissues, including neuroendocrine, liver, gut, and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. Some of its substrates include transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. This gene is thought to play a role in tumor progression and left-right patterning. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Feb 2014]
- PACE4
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~235.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0005453
Submitter: ClinGen
*PCSK6* is a key protease in the control of smooth muscle cell function in vascular remodeling. No evidence for a causal role for *PCSK6* in congenital heart disease has been reported. Protein interaction evidence has been described between PCSK6 and TBX5, where *PCSK6* is found to be downstream of *TBX5* (PMID:26744331). More evidence is needed to either support or entirely refute the role *PCSK6* plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date May 13th 2024 (SOP version 10).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PCSK6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002570.5. 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 | 7 | 1 | 9 | ||
| missense | 4 | 2 | 2 | 8 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 7 | 9 | 4 | 20 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002561.1 | 22 | MANE Select | |
| Ensembl | ENSP00000482760.1 | 22 | MANE Select | |
| RefSeq | NP_001278238.1 | 20 | Standard | |
| RefSeq | NP_612192.1 | 21 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Keratinization
- Developmental Biology
- Signal Transduction
- Transport of small molecules
- NGF processing
Biological Process
- zygotic determination of anterior/posterior axis, embryo
- determination of left/right symmetry
- glycoprotein metabolic process
- protein processing
- peptide hormone processing
Molecular Function
- endopeptidase activity
- serine-type endopeptidase activity
- protein binding
- heparin binding
- nerve growth factor binding
Cellular Component
- extracellular region
- extracellular space
- endoplasmic reticulum
- Golgi lumen
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000348070
- Coding exons
- 23
- Length
- 224588
- Individuals with no LoFs
- 125508
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 59
- Defined
- 125567
- p
- 0.000235
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.41 | 438 | 530 | 0.827 | 0.0000328 | 6206 |
| Missense (PolyPhen) | 128 | 216.64 | 0.59085 | 2300 | ||
| Synonymous | 0.588 | 209 | 220 | 0.950 | 0.0000159 | 1831 |
| Loss of Function | 3.14 | 29 | 53.9 | 0.538 | 0.00000299 | 608 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00039 | 0.00037 | rare |
| Latino/Admixed American | 0.00038 | 0.00038 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00016 | rare |
| Finnish | 0.000049 | 0.000046 | rare |
| European (Non-Finnish) | 0.00025 | 0.00025 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. Likely functions in the constitutive secretory pathway, with unique restricted distribution in both neuroendocrine and non-neuroendocrine tissues.;
Recessive Scores
- pRec
- 0.241
Essentials
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.501
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |