TSC2

TSC complex subunit 2, the group of Armadillo like helical domain containing|TSC complex|Protein phosphatase 1 regulatory subunits

Basic information

Region (hg38): 16:2047967-2089491

Previous symbols: [ "TSC4" ]

Links

ENSG00000103197 ∙ NCBI:7249 ∙ OMIM:191092 ∙ HGNC:12363 ∙ Uniprot:P49815 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• tuberous sclerosis 2 (Definitive), mode of inheritance: AD
• lymphangioleiomyomatosis (Strong), mode of inheritance: AD
• tuberous sclerosis 2 (Strong), mode of inheritance: AD
• tuberous sclerosis 2 (Strong), mode of inheritance: AD
• tuberous sclerosis 2 (Strong), mode of inheritance: AD
• tuberous sclerosis 2 (Definitive), mode of inheritance: AD
• tuberous sclerosis complex (Supportive), mode of inheritance: AD
• tuberous sclerosis (Definitive), mode of inheritance: AD
• tuberous sclerosis 2 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Tuberous sclerosis 2; Lymphangioleiomyomatosis	AD	Cardiovascular; Neurologic; Oncologic; Pulmonary; Renal	Surveillance for and early treatment of tumors, as well as other manifestations affecting multiple organ systems (eg, renal anomalies, neurologic manifestations, pulmonary manifestations, and cardiac manifestations including arrhythmias) may reduce morbidity and mortality; Treatment with mTOR inhibitors may be beneficial related to neoplastic sequelae as well as related seizures; Lymphangiomyomatosis can occur as an isolated disorder or in association with TSC - the only effective therapy in late stage disease is transplant	Cardiovascular; Dental; Dermatologic; Neurologic; Oncologic; Ophthalmologic; Pulmonary; Renal	14421523; 2823681; 3210031; 2706800; 1303246; 8162074; 8534286; 8824721; 8782048; 9302281; 9132502; 9463313; 9579160; 11829138; 14985384; 15955990; 17003820; 17005952; 17120248; 17304050; 18722871; 18032745; 19258298; 19332694; 19419980; 21266383; 21813552; 20301399; 22189265; 22490766; 23158522; 23733802; 23743818; 23757617; 23796861; 23845174; 23852707

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TSC2 gene.

• Tuberous_sclerosis_2 (9235 variants)
• Hereditary_cancer-predisposing_syndrome (5322 variants)
• Tuberous_sclerosis_syndrome (3047 variants)
• not_provided (2165 variants)
• Isolated_focal_cortical_dysplasia_type_II (838 variants)
• Lymphangiomyomatosis (647 variants)
• not_specified (645 variants)
• TSC2-related_disorder (378 variants)
• Ovarian_cancer (18 variants)
• Autism_spectrum_disorder (15 variants)
• Polycystic_kidney_disease,_adult_type (15 variants)
• Intellectual_disability (7 variants)
• Tuberous_sclerosis_1 (6 variants)
• Lung_lymphangioleiomyomatosis (5 variants)
• See_cases (4 variants)
• Seizure (3 variants)
• Cortical_tubers (3 variants)
• Dystonia,_early-onset,_and/or_spastic_paraplegia (2 variants)
• Renal_cyst (2 variants)
• Everolimus_response (2 variants)
• Dilated_cardiomyopathy_1D (1 variants)
• Arthralgia (1 variants)
• Hirschsprung_disease,_susceptibility_to,_1 (1 variants)
• Hyperextensibility_at_elbow (1 variants)
• Congenital_anomaly_of_kidney_and_urinary_tract (1 variants)
• Hyperextensible_hand_joints (1 variants)
• Tuberous_sclerosis_and_lymphangiomyomatosis (1 variants)
• Acute_myeloid_leukemia (1 variants)
• Cystic_fibrosis (1 variants)
• Focal_cortical_dysplasia (1 variants)
• Neurodevelopmental_disorder (1 variants)
• Neurodevelopmental_delay (1 variants)
• Dental_enamel_pits (1 variants)
• Neoplasm (1 variants)
• Intellectual_disability,_severe (1 variants)
• Abnormality_of_the_nervous_system (1 variants)
• Joint_hypermobility (1 variants)
• Xanthinuria_type_II (1 variants)
• Epilepsy (1 variants)
• Abnormal_cerebral_morphology (1 variants)
• Neuroblastoma (1 variants)
• Infantile_spasms (1 variants)
• Cafe-au-lait_spot (1 variants)
• Hypertrophic_cardiomyopathy_7 (1 variants)
• Vascular_dementia (1 variants)
• Rhabdomyoma (1 variants)
• Bone_osteosarcoma (1 variants)
• Recurrent_fever (1 variants)
• Vesicoureteral_reflux_8 (1 variants)
• Tall_stature (1 variants)
• Hamartoma (1 variants)
• Astroblastoma,_MN1-altered (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TSC2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000548.5. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	6	3	49	2164	161	2383
missense	71	152	3816	947	117	5103
nonsense	265	16	69	1		351
start loss		3	2			5
frameshift	549	78	382	4		1013
splice donor/acceptor (+/-2bp)	166	77	116	10	1	370
Total	1057	329	4434	3126	279

Highest pathogenic variant AF is 0.000008296118

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TSC2	protein_coding	protein_coding	ENST00000219476	41	41251

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	6.39e-13	125084	7	520	125611	0.00210

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.330	1099	1.07e+3	1.03	0.0000753	11587
Missense in Polyphen		323	396.39	0.81485		4422
Synonymous	-8.39	727	491	1.48	0.0000388	3737
Loss of Function	8.37	2	85.4	0.0234	0.00000432	1004

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00326	0.00305
Ashkenazi Jewish	0.00120	0.00119
East Asian	0.00342	0.00327
Finnish	0.000740	0.000739
European (Non-Finnish)	0.00245	0.00243
Middle Eastern	0.00342	0.00327
South Asian	0.00259	0.00255
Other	0.00180	0.00180

dbNSFP

Source: dbNSFP

• Function: FUNCTION: In complex with TSC1, this tumor suppressor inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PubMed:12271141, PubMed:28215400). Acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 (PubMed:15340059). May also play a role in microtubule-mediated protein transport (By similarity). Also stimulates the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5 (By similarity). {ECO:0000250|UniProtKB:P49816, ECO:0000269|PubMed:12271141, ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:28215400}.
• Disease: DISEASE: Tuberous sclerosis 2 (TSC2) [MIM:613254]: An autosomal dominant multi-system disorder that affects especially the brain, kidneys, heart, and skin. It is characterized by hamartomas (benign overgrowths predominantly of a cell or tissue type that occurs normally in the organ) and hamartias (developmental abnormalities of tissue combination). Clinical manifestations include epilepsy, learning difficulties, behavioral problems, and skin lesions. Seizures can be intractable and premature death can occur from a variety of disease-associated causes. {ECO:0000269|PubMed:10069705, ECO:0000269|PubMed:10205261, ECO:0000269|PubMed:10533067, ECO:0000269|PubMed:10570911, ECO:0000269|PubMed:10607950, ECO:0000269|PubMed:10732801, ECO:0000269|PubMed:10735580, ECO:0000269|PubMed:12271141, ECO:0000269|PubMed:15024740, ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:15595939, ECO:0000269|PubMed:15963462, ECO:0000269|PubMed:8824881, ECO:0000269|PubMed:9302281, ECO:0000269|PubMed:9463313, ECO:0000269|PubMed:9829910}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Lymphangioleiomyomatosis (LAM) [MIM:606690]: Progressive and often fatal lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. It affects almost exclusively young women and can occur as an isolated disorder or in association with tuberous sclerosis complex. {ECO:0000269|PubMed:10823953, ECO:0000269|PubMed:11829138}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Focal cortical dysplasia 2 (FCORD2) [MIM:607341]: A form of focal cortical dysplasia, a malformation of cortical development that results in medically refractory epilepsy in the pediatric population and in adults. FCORD2 is a severe form, with onset usually in childhood, characterized by disrupted cortical lamination and specific cytological abnormalities. It is classified in 2 subtypes: type IIA characterized by dysmorphic neurons and lack of balloon cells; type IIB with dysmorphic neurons and balloon cells. {ECO:0000269|PubMed:28215400}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Choline metabolism in cancer - Homo sapiens (human);p53 signaling pathway - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Leucine Stimulation on Insulin Signaling;AMP-activated Protein Kinase (AMPK) Signaling;Target Of Rapamycin (TOR) Signaling;Integrated Breast Cancer Pathway;Follicle Stimulating Hormone (FSH) signaling pathway;Signaling Pathways in Glioblastoma;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Nanoparticle triggered autophagic cell death;Polycystic Kidney Disease Pathway;Wnt Signaling Pathway;BDNF-TrkB Signaling;PI3K-AKT-mTOR signaling pathway and therapeutic opportunities;ATM Signaling Network in Development and Disease;Angiopoietin Like Protein 8 Regulatory Pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Pathways in clear cell renal cell carcinoma;PI3K-AKT-mTOR - VitD3 Signalling;PI3K-Akt Signaling Pathway;Insulin Signaling;Monoamine Transport;Disease;Signal Transduction;Gene expression (Transcription);mtor signaling pathway;Vesicle-mediated transport;TBC/RABGAPs;Membrane Trafficking;Generic Transcription Pathway;RNA Polymerase II Transcription;Inhibition of TSC complex formation by PKB;Energy dependent regulation of mTOR by LKB1-AMPK;mTOR signalling;insulin Mam;TP53 Regulates Metabolic Genes;Macroautophagy;Cellular responses to external stimuli;Rab regulation of trafficking;PIP3 activates AKT signaling;Transcriptional Regulation by TP53;Direct p53 effectors;Constitutive Signaling by AKT1 E17K in Cancer;PI3K/AKT Signaling in Cancer;AKT phosphorylates targets in the cytosol;Intracellular signaling by second messengers;mTOR signaling pathway;Diseases of signal transduction;Validated targets of C-MYC transcriptional repression;p38 signaling mediated by MAPKAP kinases;LKB1 signaling events;insulin (Consensus)

Recessive Scores

• pRec: 0.390

Intolerance Scores

• loftool: 0.000276
• rvis_EVS: -2.54
• rvis_percentile_EVS: 0.87

Haploinsufficiency Scores

• pHI: 0.878
• hipred: Y
• hipred_score: 0.783
• ghis: 0.602

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.856

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Tsc2
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); growth/size/body region phenotype; reproductive system 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); 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); 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); renal/urinary system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; neoplasm

Zebrafish Information Network

• Gene name: tsc2
• Affected structure: hepatocyte
• Phenotype tag: abnormal
• Phenotype quality: ballooning

Gene ontology

• Biological process: neural tube closure;negative regulation of protein kinase activity;protein import into nucleus;endocytosis;heart development;protein localization;negative regulation of cell population proliferation;negative regulation of phosphatidylinositol 3-kinase signaling;viral process;vesicle-mediated transport;positive regulation of macroautophagy;regulation of endocytosis;negative regulation of Wnt signaling pathway;negative regulation of TOR signaling;anoikis;protein kinase B signaling;positive regulation of GTPase activity;regulation of insulin receptor signaling pathway;negative regulation of insulin receptor signaling pathway;insulin-like growth factor receptor signaling pathway;positive chemotaxis;regulation of small GTPase mediated signal transduction;regulation of cell cycle;negative regulation of protein kinase B signaling;negative regulation of mitophagy
• Cellular component: nucleus;cytoplasm;lysosome;Golgi apparatus;cytosol;postsynaptic density;membrane;TSC1-TSC2 complex;perinuclear region of cytoplasm
• Molecular function: GTPase activator activity;protein binding;phosphatase binding;small GTPase binding;protein homodimerization activity;Hsp90 protein binding