PIWIL2
protein-codingpiwi like RNA-mediated gene silencing 2, the group of Piwi like RNA-mediated gene silencing family
Gene summary
PIWIL2 belongs to the Argonaute family of proteins, which function in development and maintenance of germline stem cells (Sasaki et al., 2003 [PubMed 12906857]).[supplied by OMIM, Mar 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~82.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0018393
Submitter: King Faisal Specialist Hospital and Research Center
Alhathal et al., 2020 (PMID: 32719396) reported a missense variant and a indel in a large male infertility cohort (n=285 infertile man and case–control fertile man). Gene is scored according to ClinGen classification. Strong with total score of 11. Aggregate-variant analysis (6 points), experimental evidence: Animal model (4 points). Testicular expression (1 points) (PMID: 14736746).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PIWIL2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018068.5. 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 | 0 | |||||
| missense | 145 | 11 | 156 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 145 | 11 | 0 | 156 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060538.2 | 22 | MANE Select | |
| Ensembl | ENSP00000349208.6 | 22 | MANE Select | |
| RefSeq | NP_001129193.1 | 22 | Standard | |
| RefSeq | NP_001317409.1 | 21 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| piwil2 | Danio rerio | Structure: post-vent region Quality: decreased length abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Gene expression (Transcription)
- PIWI-interacting RNA (piRNA) biogenesis
- Gene Silencing by RNA
Biological Process
- RNA 5'-end processing
- multicellular organism development
- spermatogenesis
- negative regulation of transposition
- germ-line stem cell population maintenance
Molecular Function
- mRNA binding
- endoribonuclease activity
- piRNA binding
- metal ion binding
- polysome binding
Cellular Component
- nucleus
- cytoplasm
- perinucleolar chromocenter
- chromatoid body
- P granule
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000356766
- Coding exons
- 22
- Length
- 82267
- Individuals with no LoFs
- 125656
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 92
- Defined
- 125748
- p
- 0.000366
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.119 | 553 | 545 | 1.01 | 0.0000293 | 6384 |
| Missense (PolyPhen) | 100 | 147.89 | 0.67619 | 1730 | ||
| Synonymous | -0.153 | 201 | 198 | 1.01 | 0.0000107 | 1888 |
| Loss of Function | 3.85 | 22 | 52.0 | 0.423 | 0.00000275 | 600 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00033 | 0.00032 | rare |
| Ashkenazi Jewish | 0.00089 | 0.00089 | rare |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.0017 | 0.0017 | notable |
| European (Non-Finnish) | 0.00020 | 0.00020 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Endoribonuclease that plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity (By similarity). Plays an essential role in meiotic differentiation of spermatocytes, germ cell differentiation and in self-renewal of spermatogonial stem cells (By similarity). Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons (By similarity). During piRNA biosynthesis, plays a key role in the piRNA amplification loop, also named ping-pong amplification cycle, by acting as a 'slicer- competent' piRNA endoribonuclease that cleaves primary piRNAs, which are then loaded onto 'slicer-incompetent' PIWIL4 (By similarity). PIWIL2 slicing produces a pre-miRNA intermediate, which is then processed in mature piRNAs, and as well as a 16 nucleotide by-product that is degraded (By similarity). Required for PIWIL4/MIWI2 nuclear localization and association with secondary piRNAs antisense (By similarity). Besides their function in transposable elements repression, piRNAs are probably involved in other processes during meiosis such as translation regulation (By similarity). Indirectly modulates expression of genes such as PDGFRB, SLC2A1, ITGA6, GJA7, THY1, CD9 and STRA8 (By similarity). When overexpressed, acts as an oncogene by inhibition of apoptosis and promotion of proliferation in tumors (PubMed:16377660). {ECO:0000250|UniProtKB:Q8CDG1, ECO:0000269|PubMed:16377660}.;
Recessive Scores
- pRec
- 0.0867
Intolerance Scores
- LoFtool
- 0.817
- RVIS EVS
- -0.35
- RVIS percentile EVS
- 29.61
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.215
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |