AKAP9

protein-coding

A-kinase anchoring protein 9, the group of A-kinase anchoring proteins|Protein phosphatase 1 regulatory subunits

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. Alternate splicing of this gene results in at least two isoforms that localize to the centrosome and the Golgi apparatus, and interact with numerous signaling proteins from multiple signal transduction pathways. These signaling proteins include type II protein kinase A, serine/threonine kinase protein kinase N, protein phosphatase 1, protein phosphatase 2a, protein kinase C-epsilon and phosphodiesterase 4D3. [provided by RefSeq, Aug 2008]

MANE transcript

NM_005751.5

Inheritance

AR, AD

ClinVar variants

P:4U:2007B:1284

Top phenotype

Long QT syndrome 11

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr7:91,940,840-92,110,673

External References & Databases

Ensembl (ENSG00000127914)

Transcript & Mutation Effects

hg38 • Region Span ~169.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

male infertility with azoospermia or oligozoospermia due to single gene mutationMODERATE

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 in a large male infertility cohort (n=285 infertile man and case–control fertile man). The gene is scored according to ClinGen classification. Moderate with total score of 8. Single-variant analysis (3 points), experimental evidence: Animal model (4 points) and testicular expression (1 points) (PMID: 23608191).

long QT syndrome 11LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012738

Submitter: Ambry Genetics

long QT syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0002442

Submitter: ClinGen

AKAP9 encodes A-kinase anchor protein 9, a scaffold protein that binds to the slowly activating cardiac potassium channel (Iks) and is important for its physiological response to sympathetic stimulation. The first study to associate this gene with LQTS used a candidate gene approach and identified a missense variant in AKAP9 in a single patient with LQTS (PMID 18093912). However, because of the candidate gene approach, lack of segregation or case-control data and paucity of additional genetic and experimental data, this gene-disease association was classified as disputed. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams were reviewed by the LQTS Clinical Domain Expert Panel. For a detailed discussion of this group's work and the separate scores of the 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”

long QT syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0002442

Submitter: G2P

long QT syndrome 11LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012738

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Long QT syndrome 11AD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: In order to prevent sequelae including syncope, cardiac arrest and sudden death prophylactic use of beta blockers in asymptomatic individuals may be beneficial; ICD may be indicated for individuals refractory to beta-blocker treatment or with history of cardiac arrest; Agents that can contribute to prolonged QT or related dysrhythmias should be avoided, as should activities associated with high stress/intense exertion

Refs: 10220144; 18093912; 20809527; 21430528; 20301308

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AKAP9 variants in ClinVar

26 Conditions Cataloged

Cardiovascular phenotypeTotal: 2400

Long QT syndromeTotal: 2235

not providedTotal: 405

not specifiedTotal: 346

Long QT syndrome 11Total: 275

AKAP9-related disorderTotal: 84

CardiomyopathyTotal: 11

Long QT syndrome 1Total: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005751.5. 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			19 clinvar	813 clinvar	4 clinvar	836
missense		2 clinvar	1806 clinvar	453 clinvar	9 clinvar	2270
nonsense		2 clinvar	57 clinvar	1 clinvar		60
start loss			1 clinvar			1
frameshift			77 clinvar	1 clinvar	3 clinvar	81
splice donor/acceptor (+/-2bp)			47 clinvar			47
Total	0	4	2007	1268	16	3295

Highest pathogenic variant AF is 0.0000047886692

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005751.5	RefSeq	NP_005742.4	50	MANE Select
ENST00000356239.8	Ensembl	ENSP00000348573.3	50	MANE Select
NM_001379277.1	RefSeq	NP_001366206.1	29	Standard
NM_147185.3	RefSeq	NP_671714.1	50	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

G Protein Signaling Pathways
NO-cGMP-PKG mediated Neuroprotection
Disease
Signal Transduction
protein kinase a at the centrosome

Biological Process

G2/M transition of mitotic cell cycle
microtubule nucleation
signal transduction
negative regulation of adenylate cyclase activity
chemical synaptic transmission

Molecular Function

DNA binding
signaling receptor binding
protein binding
potassium channel regulator activity
protein-containing complex scaffold activity

Cellular Component

Golgi apparatus
Golgi stack
cis-Golgi network
centrosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356239
Coding exons: 50
Length: 169807
Individuals with no LoFs: 125545
Homozygous LoFs: 0
Heterozygous LoFs: 203
Defined: 125748
p: 0.000807

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.128	1850	1.83e+3	1.01	0.0000895	25902
Missense (PolyPhen)		588	654.49	0.89841		9778
Synonymous	0.762	625	650	0.962	0.0000317	6822
Loss of Function	9.06	71	214	0.332	0.0000115	2680

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00062	0.00062	rare
Latino/Admixed American	0.00075	0.00075	rare
Ashkenazi Jewish	0.00021	0.00020	rare
East Asian	0.00049	0.00049	rare
Finnish	0.0012	0.0012	notable
European (Non-Finnish)	0.00096	0.00095	rare
South Asian	0.00073	0.00072	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Scaffolding protein that assembles several protein kinases and phosphatases on the centrosome and Golgi apparatus. Required to maintain the integrity of the Golgi apparatus (PubMed:10202149, PubMed:15047863). Required for microtubule nucleation at the cis-side of the Golgi apparatus (PubMed:15047863, PubMed:19242490). Required for association of the centrosomes with the poles of the bipolar mitotic spindle during metaphase (PubMed:25657325). In complex with PDE4DIP isoform 13/MMG8/SMYLE, recruits CAMSAP2 to the Golgi apparatus and tethers non-centrosomal minus-end microtubules to the Golgi, an important step for polarized cell movement (PubMed:27666745, PubMed:28814570). In complex with PDE4DIP isoform 13/MMG8/SMYLE, EB1/MAPRE1 and CDK5RAP2, contributes to microtubules nucleation and extension also from the centrosome to the cell periphery (PubMed:29162697). {ECO:0000269|PubMed:10202149, ECO:0000269|PubMed:15047863, ECO:0000269|PubMed:19242490, ECO:0000269|PubMed:25657325, ECO:0000269|PubMed:27666745, ECO:0000269|PubMed:28814570, ECO:0000269|PubMed:29162697}.;
Disease: DISEASE: Long QT syndrome 11 (LQT11) [MIM:611820]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. {ECO:0000269|PubMed:18093912}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.111

Intolerance Scores

LoFtool: 0.933
RVIS EVS: 0.22
RVIS percentile EVS: 68.45

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.444

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High