AKT2
AKT serine/threonine kinase 2, the group of AKT kinases|Pleckstrin homology domain containing|MicroRNA protein coding host genes
Basic information
Region (hg38): 19:40230317-40285536
Links
Phenotypes
GenCC
Source:
- AKT2-related familial partial lipodystrophy (Supportive), mode of inheritance: AD
- hypoinsulinemic hypoglycemia and body hemihypertrophy (Supportive), mode of inheritance: AD
- hypoinsulinemic hypoglycemia and body hemihypertrophy (Definitive), mode of inheritance: AD
- type 2 diabetes mellitus (Limited), mode of inheritance: AD
- hypoinsulinemic hypoglycemia and body hemihypertrophy (Strong), mode of inheritance: AD
- diabetes mellitus, noninsulin-dependent (Strong), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Hypoinsulinemic hypoglycemia with hemihypertrophy | AD | Endocrine | Individuals may present early in life with severe hypoglycemia (and related sequelae, including seizures and death), and in order to prevent severe hypoglycemia, specific feeding regimens (eg, overnight enteral carbohydrate feeding) may be beneficial | Endocrine; Musculoskeletal | 15166380; 14764948; 19164855; 21979934 |
ClinVar
This is a list of variants' phenotypes submitted to
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the AKT2 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 35 | 42 | ||||
| missense | 43 | 46 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| inframe indel | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | |||||
| splice region | 5 | 11 | 16 | |||
| non coding | 22 | 27 | 50 | |||
| Total | 0 | 1 | 50 | 59 | 29 |
Variants in AKT2
This is a list of pathogenic ClinVar variants found in the AKT2 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 19-40233606-A-G | Benign (Nov 10, 2018) | |||
| 19-40233814-G-T | Benign (Nov 10, 2018) | |||
| 19-40233863-G-A | not specified | Benign/Likely benign (Mar 30, 2021) | ||
| 19-40233868-C-G | AKT2-related disorder | Likely benign (Aug 30, 2019) | ||
| 19-40233905-G-C | Type 2 diabetes mellitus;Hypoinsulinemic hypoglycemia and body hemihypertrophy | Likely benign (Dec 20, 2022) | ||
| 19-40233919-G-A | Hypoinsulinemic hypoglycemia and body hemihypertrophy;Type 2 diabetes mellitus • not specified | Conflicting classifications of pathogenicity (Nov 06, 2023) | ||
| 19-40233958-G-A | Hypoinsulinemic hypoglycemia and body hemihypertrophy;Type 2 diabetes mellitus • not specified | Likely benign (Dec 07, 2023) | ||
| 19-40233960-G-A | AKT2-related disorder | Likely benign (May 28, 2019) | ||
| 19-40234939-T-C | Likely benign (Mar 01, 2024) | |||
| 19-40235025-C-T | Hypoinsulinemic hypoglycemia and body hemihypertrophy;Type 2 diabetes mellitus | Benign/Likely benign (Jan 08, 2024) | ||
| 19-40235026-G-A | Type 2 diabetes mellitus;Hypoinsulinemic hypoglycemia and body hemihypertrophy | Likely benign (Sep 26, 2023) | ||
| 19-40235048-G-A | Hypoinsulinemic hypoglycemia and body hemihypertrophy;Type 2 diabetes mellitus | Uncertain significance (Jun 13, 2023) | ||
| 19-40235079-G-A | Likely benign (Mar 29, 2018) | |||
| 19-40235100-C-T | Hypoinsulinemic hypoglycemia and body hemihypertrophy;Type 2 diabetes mellitus | Likely benign (Dec 26, 2023) | ||
| 19-40235115-G-A | Type 2 diabetes mellitus;Hypoinsulinemic hypoglycemia and body hemihypertrophy | Benign (Aug 04, 2023) | ||
| 19-40235119-G-A | Uncertain significance (Feb 16, 2023) | |||
| 19-40235125-T-C | Hypoinsulinemic hypoglycemia and body hemihypertrophy;Type 2 diabetes mellitus | Uncertain significance (Jan 21, 2020) | ||
| 19-40235130-T-C | AKT2-related disorder | Likely benign (Aug 22, 2022) | ||
| 19-40235151-C-A | Type 2 diabetes mellitus;Hypoinsulinemic hypoglycemia and body hemihypertrophy | Likely benign (Mar 25, 2021) | ||
| 19-40235151-C-T | Type 2 diabetes mellitus;Hypoinsulinemic hypoglycemia and body hemihypertrophy | Likely benign (Nov 12, 2022) | ||
| 19-40235280-C-T | Inborn genetic diseases | Uncertain significance (Sep 13, 2017) | ||
| 19-40235299-G-A | Type 2 diabetes mellitus;Hypoinsulinemic hypoglycemia and body hemihypertrophy | Likely benign (Oct 04, 2022) | ||
| 19-40235340-C-G | Inborn genetic diseases | Uncertain significance (Nov 23, 2020) | ||
| 19-40235360-G-C | Type 2 diabetes mellitus;Hypoinsulinemic hypoglycemia and body hemihypertrophy | Likely benign (Nov 22, 2022) | ||
| 19-40235362-C-T | Type 2 diabetes mellitus;Hypoinsulinemic hypoglycemia and body hemihypertrophy | Likely benign (Jul 19, 2022) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| AKT2 | protein_coding | protein_coding | ENST00000392038 | 13 | 55220 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.644 | 0.356 | 125735 | 0 | 10 | 125745 | 0.0000398 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 2.41 | 186 | 305 | 0.611 | 0.0000216 | 3181 |
| Missense in Polyphen | 55 | 128.67 | 0.42744 | 1390 | ||
| Synonymous | -0.889 | 135 | 122 | 1.10 | 0.00000927 | 906 |
| Loss of Function | 3.73 | 5 | 25.2 | 0.199 | 0.00000119 | 297 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.0000289 | 0.0000289 |
| Ashkenazi Jewish | 0.0000992 | 0.0000992 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000707 | 0.0000703 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.00 | 0.00 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: AKT2 is one of 3 closely related serine/threonine- protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)- response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development.;
- Disease
- DISEASE: Note=Defects in AKT2 are a cause of susceptibility to breast cancer (BC). AKT2 promotes metastasis of tumor cells without affecting the latency of tumor development. With AKT3, plays also a pivotal role in the biology of glioblastoma.; DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15166380, ECO:0000269|PubMed:19164855}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hypoinsulinemic hypoglycemia with hemihypertrophy (HIHGHH) [MIM:240900]: A disorder characterized by hypoglycemia, low insulin levels, low serum levels of ketone bodies and branched-chain amino acids, left-sided hemihypertrophy, neonatal macrosomia, reduced consciousness and hypoglycemic seizures. {ECO:0000269|PubMed:21979934}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- PKB-mediated events;PI3K-Akt signaling pathway - Homo sapiens (human);Non-small cell lung cancer - Homo sapiens (human);Platelet activation - Homo sapiens (human);Chronic myeloid leukemia - Homo sapiens (human);Gastric cancer - Homo sapiens (human);Focal adhesion - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);Regulation of lipolysis in adipocytes - Homo sapiens (human);Adipocytokine signaling pathway - Homo sapiens (human);T cell receptor signaling pathway - Homo sapiens (human);B cell receptor signaling pathway - Homo sapiens (human);Fc epsilon RI signaling pathway - Homo sapiens (human);Fc gamma R-mediated phagocytosis - Homo sapiens (human);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Renal cell carcinoma - Homo sapiens (human);VEGF signaling pathway - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Central carbon metabolism in cancer - Homo sapiens (human);Choline metabolism in cancer - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Melanoma - Homo sapiens (human);Insulin resistance - Homo sapiens (human);Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Jak-STAT signaling pathway - Homo sapiens (human);Longevity regulating pathway - multiple species - Homo sapiens (human);Small cell lung cancer - Homo sapiens (human);Influenza A - Homo sapiens (human);Acute myeloid leukemia - Homo sapiens (human);Breast cancer - Homo sapiens (human);ErbB signaling pathway - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);Carbohydrate digestion and absorption - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Glucagon signaling pathway - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Glioma - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Prostate cancer - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Fluid shear stress and atherosclerosis - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Tuberculosis - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Sphingolipid signaling pathway - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);Prolactin signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Measles - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Apoptosis - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);Endometrial cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);EGFR Inhibitor Pathway, Pharmacodynamics;Human papillomavirus infection - Homo sapiens (human);Progesterone-mediated oocyte maturation - Homo sapiens (human);VEGF Signaling Pathway;IGF-Core;AMP-activated Protein Kinase (AMPK) Signaling;Regulation of toll-like receptor signaling pathway;MicroRNAs in cardiomyocyte hypertrophy;TFs Regulate miRNAs related to cardiac hypertrophy;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;Integrin-mediated Cell Adhesion;TNF related weak inducer of apoptosis (TWEAK) Signaling Pathway;Signaling Pathways in Glioblastoma;Signal Transduction of S1P Receptor;Cardiac Hypertrophic Response;Focal Adhesion;MAPK Signaling Pathway;Angiopoietin Like Protein 8 Regulatory Pathway;Chemokine signaling pathway;ESC Pluripotency Pathways;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Lipid Metabolism Pathway;Steatosis AOP;Endometrial cancer;PI3K-Akt Signaling Pathway;MET in type 1 papillary renal cell carcinoma;Chromosomal and microsatellite instability in colorectal cancer;Ras Signaling;EMT transition in Colorectal Cancer;Insulin Signaling;DNA Damage Response (only ATM dependent);Toll-like Receptor Signaling Pathway;Developmental Biology;Signaling by GPCR;TWEAK;RUNX2 regulates genes involved in cell migration;Transcriptional regulation by RUNX2;Disease;Signaling by WNT;Signal Transduction;Gene expression (Transcription);Vesicle-mediated transport;VEGFA-VEGFR2 Pathway;Membrane Trafficking;Generic Transcription Pathway;Regulation of PTEN stability and activity;Activation of AKT2;PDE3B signalling;CD28 dependent PI3K/Akt signaling;CD28 co-stimulation;CTLA4 inhibitory signaling;PI3K Cascade;Costimulation by the CD28 family;IRS-mediated signalling;Insulin receptor signalling cascade;Signaling by Insulin receptor;RNA Polymerase II Transcription;Inhibition of TSC complex formation by PKB;Activation of BAD and translocation to mitochondria ;mTOR signalling;Activation of BH3-only proteins;Intrinsic Pathway for Apoptosis;IGF signaling;Immune System;Apoptosis;Programmed Cell Death;Adaptive Immune System;Cyclin E associated events during G1/S transition ;AKT phosphorylates targets in the nucleus;insulin Mam;Mitotic G1-G1/S phases;Cyclin A:Cdk2-associated events at S phase entry;TP53 Regulates Metabolic Genes;S Phase;Deactivation of the beta-catenin transactivating complex;Downregulation of ERBB2:ERBB3 signaling;Downregulation of ERBB2 signaling;IL-7 signaling;Rab regulation of trafficking;Regulation of TP53 Degradation;Regulation of TP53 Expression and Degradation;PTEN Regulation;PIP3 activates AKT signaling;JAK STAT pathway and regulation;PDGF;E-cadherin signaling in keratinocytes;G1/S Transition;EPO signaling;Regulation of TP53 Activity through Association with Co-factors;Regulation of TP53 Activity through Acetylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Negative regulation of the PI3K/AKT network;Signaling by VEGF;Signaling by ERBB2;Constitutive Signaling by AKT1 E17K in Cancer;PI3K/AKT Signaling in Cancer;RAB GEFs exchange GTP for GDP on RABs;Cell Cycle;IRS-related events triggered by IGF1R;IGF1R signaling cascade;TNFalpha;Translocation of GLUT4 to the plasma membrane;Signaling by Receptor Tyrosine Kinases;AKT phosphorylates targets in the cytosol;VEGF;Cell Cycle, Mitotic;G beta:gamma signalling through PI3Kgamma;G-protein beta:gamma signalling;GPCR downstream signalling;Intracellular signaling by second messengers;Insulin Pathway;Diseases of signal transduction;Insulin-mediated glucose transport;Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met);Regulation of beta-cell development;TCF dependent signaling in response to WNT;Class I PI3K signaling events mediated by Akt;Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R);CD4 T cell receptor signaling-NFkB cascade;VEGFR2 mediated vascular permeability;AKT-mediated inactivation of FOXO1A;Regulation of gene expression in beta cells;insulin;FSH;CD4 T cell receptor signaling
(Consensus)
Recessive Scores
- pRec
- 0.556
Intolerance Scores
- loftool
- 0.324
- rvis_EVS
- -0.65
- rvis_percentile_EVS
- 16.36
Haploinsufficiency Scores
- pHI
- 0.920
- hipred
- Y
- hipred_score
- 0.831
- ghis
- 0.646
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.983
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Akt2
- Phenotype
- integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype; reproductive system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; neoplasm; liver/biliary system phenotype; respiratory system phenotype; immune system phenotype; skeleton phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan);
Zebrafish Information Network
- Gene name
- akt2
- Affected structure
- head
- Phenotype tag
- abnormal
- Phenotype quality
- opaque
Gene ontology
- Biological process
- positive regulation of protein phosphorylation;glycogen biosynthetic process;glucose metabolic process;regulation of translation;cellular protein modification process;signal transduction;positive regulation of cell population proliferation;insulin receptor signaling pathway;carbohydrate transport;negative regulation of plasma membrane long-chain fatty acid transport;positive regulation of glucose metabolic process;positive regulation of mitochondrial membrane potential;peptidyl-serine phosphorylation;regulation of cell migration;positive regulation of cell migration;positive regulation of vesicle fusion;positive regulation of fatty acid beta-oxidation;peripheral nervous system myelin maintenance;cellular response to insulin stimulus;intracellular signal transduction;negative regulation of apoptotic process;protein kinase B signaling;fat cell differentiation;positive regulation of glycogen biosynthetic process;positive regulation of glucose import;mammary gland epithelial cell differentiation;intracellular protein transmembrane transport;regulation of cell cycle arrest;cellular response to high light intensity;protein localization to plasma membrane;positive regulation of protein targeting to membrane;activation of GTPase activity;retinal rod cell apoptotic process;positive regulation of cell motility
- Cellular component
- nucleus;nucleoplasm;early endosome;cytosol;plasma membrane;cell cortex;ruffle membrane;protein-containing complex;intracellular membrane-bounded organelle
- Molecular function
- protein serine/threonine kinase activity;protein binding;ATP binding;metal ion binding