AKAP13
protein-codingA-kinase anchoring protein 13, the group of Dbl family Rho GEFs|A-kinase anchoring proteins|Pleckstrin homology domain containing|MicroRNA protein coding host genes|Minor histocompatibility antigens
Gene summary
The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms containing c-terminal dbl oncogene homology (DH) and pleckstrin homology (PH) domains. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. Therefore, these isoforms function as scaffolding proteins to coordinate a Rho signaling pathway, function as protein kinase A-anchoring proteins and, in addition, enhance ligand-dependent activity of estrogen receptors alpha and beta. [provided by RefSeq, Jul 2012]
- LBC
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~368.8 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 AKAP13 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_007200.5. 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 | 6 | 11 | 9 | 26 | ||
| missense | 468 | 35 | 4 | 507 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 0 | 0 | 478 | 46 | 13 | 537 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_009131.2 | 36 | MANE Select | |
| Ensembl | ENSP00000378026.3 | 36 | MANE Select | |
| RefSeq | NP_001257475.1 | 29 | Standard | |
| RefSeq | NP_006729.4 | 36 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glucocorticoid Receptor Pathway
- Nuclear Receptors Meta-Pathway
- G Protein Signaling Pathways
- Signaling by GPCR
- Signal Transduction
Biological Process
- protein phosphorylation
- G protein-coupled receptor signaling pathway
- heart development
- positive regulation of Rho protein signal transduction
- positive regulation of apoptotic process
Molecular Function
- cAMP-dependent protein kinase activity
- MAP-kinase scaffold activity
- guanyl-nucleotide exchange factor activity
- Rho guanyl-nucleotide exchange factor activity
- protein binding
Cellular Component
- nucleus
- cytosol
- actin filament
- cell cortex
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361243
- Coding exons
- 36
- Length
- 368785
- Individuals with no LoFs
- 125640
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 108
- Defined
- 125748
- p
- 0.000430
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.64 | 1700 | 1.52e+3 | 1.12 | 0.0000823 | 18512 |
| Missense (PolyPhen) | 430 | 448.95 | 0.95779 | 5611 | ||
| Synonymous | -3.54 | 677 | 570 | 1.19 | 0.0000318 | 5516 |
| Loss of Function | 7.97 | 25 | 119 | 0.211 | 0.00000643 | 1466 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0023 | 0.0023 | notable |
| Latino/Admixed American | 0.00046 | 0.00046 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00038 | 0.00038 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Scaffold protein that plays an important role in assembling signaling complexes downstream of several types of G protein-coupled receptors. Activates RHOA in response to signaling via G protein-coupled receptors via its function as Rho guanine nucleotide exchange factor (PubMed:11546812, PubMed:15229649, PubMed:23090968, PubMed:25186459, PubMed:24993829). May also activate other Rho family members (PubMed:11546812). Part of a kinase signaling complex that links ADRA1A and ADRA1B adrenergic receptor signaling to the activation of downstream p38 MAP kinases, such as MAPK11 and MAPK14 (PubMed:17537920, PubMed:23716597, PubMed:21224381). Part of a signaling complex that links ADRA1B signaling to the activation of RHOA and IKBKB/IKKB, leading to increased NF-kappa-B transcriptional activity (PubMed:23090968). Part of a RHOA-dependent signaling cascade that mediates responses to lysophosphatidic acid (LPA), a signaling molecule that activates G-protein coupled receptors and potentiates transcriptional activation of the glucocorticoid receptor NR3C1 (PubMed:16469733). Part of a signaling cascade that stimulates MEF2C-dependent gene expression in response to lysophosphatidic acid (LPA) (By similarity). Part of a signaling pathway that activates MAPK11 and/or MAPK14 and leads to increased transcription activation of the estrogen receptors ESR1 and ESR2 (PubMed:9627117, PubMed:11579095). Part of a signaling cascade that links cAMP and EGFR signaling to BRAF signaling and to PKA- mediated phosphorylation of KSR1, leading to the activation of downstream MAP kinases, such as MAPK1 or MAPK3 (PubMed:21102438). Functions as scaffold protein that anchors cAMP-dependent protein kinase (PKA) and PRKD1. This promotes activation of PRKD1, leading to increased phosphorylation of HDAC5 and ultimately cardiomyocyte hypertrophy (By similarity). Has no guanine nucleotide exchange activity on CDC42, Ras or Rac (PubMed:11546812). Required for normal embryonic heart development, and in particular for normal sarcomere formation in the developing cardiomyocytes (By similarity). Plays a role in cardiomyocyte growth and cardiac hypertrophy in response to activation of the beta-adrenergic receptor by phenylephrine or isoproterenol (PubMed:17537920, PubMed:23090968). Required for normal adaptive cardiac hypertrophy in response to pressure overload (PubMed:23716597). Plays a role in osteogenesis (By similarity). {ECO:0000250|UniProtKB:E9Q394, ECO:0000269|PubMed:11546812, ECO:0000269|PubMed:11579095, ECO:0000269|PubMed:17537920, ECO:0000269|PubMed:21224381, ECO:0000269|PubMed:23716597, ECO:0000269|PubMed:24993829, ECO:0000269|PubMed:25186459, ECO:0000269|PubMed:9627117, ECO:0000269|PubMed:9891067}.;
Recessive Scores
- pRec
- 0.220
Intolerance Scores
- LoFtool
- 0.0693
- RVIS EVS
- 1.99
- RVIS percentile EVS
- 97.64
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.956
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | High | Medium | High |
| Cancer | High | Medium | High |