PACSIN3
protein-codingprotein kinase C and casein kinase substrate in neurons 3, the group of F-BAR domain containing |MicroRNA protein coding host genes
Gene summary
This gene is a member of the protein kinase C and casein kinase substrate in neurons family. The encoded protein is involved in linking the actin cytoskeleton with vesicle formation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~8.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0005336
Submitter: LiferaOmics
Genetic evidence – Published PMID: 38637313 – Reports three affected individuals from two unrelated families. Family 1 – one proband. (biallelic predicted null in AR model; homozygous/compound heterozygous; no deduction applied) = 1.5; Segregation = 0; Case-control = 0. Family 1 total = 1.5 Family 2 – two affected siblings from a consanguineous family. (Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = 1.0; Segregation (affected sibling; conservative assignment) = 0.5; Case-control = 0. Family 2 total = 1.5 PMID: 38637313 total = 3.0 Published genetic evidence total = 3.0 / 12 Genetic evidence – Our Case Family 1 – one proband; (Note: Coexisting ARSB-related MPS VI diagnosis present; PACSIN3 variant interpreted as contributor to hyperCKaemia/myopathic phenotype.) Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = 1.0; Segregation = 0; Case-control = 0. Family 1 total = 1.0 Our Case Total = 1.0 / 12 Updated Total Genetic Evidence (Published + Our Case) Published genetic evidence: 3.0 Our additional case: 1.0 Updated genetic total = 4.0 / 12 Experimental Evidence – Published PMID: 29202928 – PACSIN3 (syndapin III) knockout mouse demonstrates marked reduction of caveolae in skeletal muscle and exercise-induced muscle pathology, supporting a membrane/caveolar mechanism relevant to myopathy. Gene function / biological plausibility (caveolae biology in muscle integrity) = 1.5 Animal/model evidence (skeletal muscle structural vulnerability in KO mouse) = 2.0 Experimental evidence total = 2.5 / 6 Updated Overall Score Genetic evidence = 4.0 Experimental evidence = 3.5 Updated total = 7.5 / 18
Inheritance Pattern: AR
Disease ID:MONDO:0005336
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0005336
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PACSIN3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016223.5. 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 | 86 | 1 | 87 | |||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 3 | 0 | 87 | 2 | 0 | 92 |
Highest pathogenic variant AF is 0.000018698975
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057307.2 | 9 | MANE Select | |
| Ensembl | ENSP00000298838.6 | 9 | MANE Select | |
| RefSeq | NP_001171903.1 | 9 | Standard | |
| RefSeq | NP_001171904.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pacsin3 | Danio rerio | Structure: post-vent region Quality: bent abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Vesicle-mediated transport
- Membrane Trafficking
- Clathrin-mediated endocytosis
Biological Process
- endocytosis
- cytoskeleton organization
- negative regulation of endocytosis
- positive regulation of membrane protein ectodomain proteolysis
- negative regulation of calcium ion transport
Molecular Function
- protein binding
- phospholipid binding
- cytoskeletal protein binding
- lipid binding
- calcium channel inhibitor activity
Cellular Component
- cytoplasm
- cytosol
- cytoskeleton
- plasma membrane
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000539589
- Coding exons
- 9
- Length
- 8919
- Individuals with no LoFs
- 125708
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 36
- Defined
- 125744
- p
- 0.000143
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.776 | 256 | 293 | 0.872 | 0.0000209 | 2763 |
| Missense (PolyPhen) | 81 | 111.37 | 0.72733 | 1118 | ||
| Synonymous | 0.623 | 108 | 117 | 0.927 | 0.00000808 | 809 |
| Loss of Function | 2.90 | 9 | 24.5 | 0.368 | 0.00000122 | 252 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00037 | 0.00037 | rare |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00013 | 0.00012 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a role in endocytosis and regulates internalization of plasma membrane proteins. Overexpression impairs internalization of SLC2A1/GLUT1 and TRPV4 and increases the levels of SLC2A1/GLUT1 and TRPV4 at the cell membrane. Inhibits the TRPV4 calcium channel activity (By similarity). {ECO:0000250, ECO:0000269|PubMed:11082044}.;
Recessive Scores
- pRec
- 0.202
Intolerance Scores
- LoFtool
- 0.738
- RVIS EVS
- -0.53
- RVIS percentile EVS
- 20.78
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.849
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |