NTRK2

neurotrophic receptor tyrosine kinase 2, the group of Receptor tyrosine kinases|I-set domain containing

Basic information

Region (hg38): 9:84668375-85095751

Links

ENSG00000148053 ∙ NCBI:4915 ∙ OMIM:600456 ∙ HGNC:8032 ∙ Uniprot:Q16620 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• obesity, hyperphagia, and developmental delay (Strong), mode of inheritance: AD
• West syndrome (Supportive), mode of inheritance: AD
• undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
• developmental and epileptic encephalopathy, 58 (Strong), mode of inheritance: AD
• obesity, hyperphagia, and developmental delay (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Obesity, hyperphagia, and developmental delay	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Endocrine; Neurologic	15494731; 27884935; 29100083

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NTRK2 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NTRK2 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				177	4	181
missense		4	230	8		242
nonsense		1	5			6
start loss						0
frameshift			3			3
inframe indel			2			2
splice donor/acceptor (+/-2bp)			5			5
splice region			15	26	3	44
non coding			2	76	28	106
Total	0	5	247	261	32

Variants in NTRK2

This is a list of pathogenic ClinVar variants found in the NTRK2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-84670322-A-G			Benign (Jun 20, 2021)
9-84670680-C-G			Benign (Nov 12, 2018)
9-84670739-G-C		NTRK2-related disorder	Likely benign (Mar 24, 2022)
9-84670750-TGTC-T			Uncertain significance (Apr 10, 2022)
9-84670753-C-G			Uncertain significance (May 24, 2022)
9-84670754-G-A			Likely benign (Aug 12, 2022)
9-84670754-G-C			Likely benign (Nov 08, 2022)
9-84670754-G-T			Likely benign (Jul 17, 2023)
9-84670766-G-A			Likely benign (Apr 03, 2021)
9-84670773-G-A		Developmental and epileptic encephalopathy, 58 • Inborn genetic diseases • NTRK2-related disorder	Uncertain significance (Aug 20, 2023)
9-84670775-A-G		NTRK2-related disorder	Likely benign (Nov 30, 2021)
9-84670776-C-G			Uncertain significance (Jan 13, 2023)
9-84670777-C-A			Uncertain significance (Sep 19, 2023)
9-84670778-C-T		NTRK2-related disorder	Likely benign (Dec 14, 2022)
9-84670779-G-T		not specified • NTRK2-related disorder	Conflicting classifications of pathogenicity (Dec 31, 2023)
9-84670787-G-A		NTRK2-related disorder	Likely benign (Nov 27, 2023)
9-84670788-C-T			Uncertain significance (May 20, 2023)
9-84670792-T-A			Uncertain significance (Aug 31, 2021)
9-84670804-G-A		NTRK2-related disorder	Uncertain significance (Aug 18, 2022)
9-84670805-C-T		NTRK2-related disorder	Likely benign (May 10, 2024)
9-84670813-T-C			Uncertain significance (Jun 23, 2023)
9-84670815-G-A		Inborn genetic diseases	Uncertain significance (Dec 04, 2023)
9-84670832-C-G			Likely benign (Dec 06, 2023)
9-84670832-C-T			Likely benign (Jun 05, 2022)
9-84670834-C-T		Inborn genetic diseases	Uncertain significance (Apr 28, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NTRK2	protein_coding	protein_coding	ENST00000376214	18	355040

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000120	125704	0	2	125706	0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.73	244	472	0.516	0.0000276	5565
Missense in Polyphen		63	231.41	0.27224		2768
Synonymous	-0.215	197	193	1.02	0.0000133	1579
Loss of Function	5.89	1	42.4	0.0236	0.00000229	480

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity. Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin- 4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin- dependent calcium signaling in glial cells and mediate communication between neurons and glia. {ECO:0000269|PubMed:15494731}.
• Disease: DISEASE: Epileptic encephalopathy, early infantile, 58 (EIEE58) [MIM:617830]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE58 is an autosomal dominant condition characterized by onset of refractory seizures in the first days or months of life. {ECO:0000269|PubMed:29100083}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Obesity, hyperphagia, and developmental delay (OBHD) [MIM:613886]: A disorder characterized by early-onset obesity, hyperphagia, and severe developmental delay in motor function, speech, and language. {ECO:0000269|PubMed:15494731, ECO:0000269|PubMed:27884935, ECO:0000269|PubMed:29100083}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);Neurotrophin signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Alcoholism - Homo sapiens (human);Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;BDNF-TrkB Signaling;MAPK Signaling Pathway;ERK Pathway in Huntington,s Disease;PI3K-Akt Signaling Pathway;Ras Signaling;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Activation of TRKA receptors;Signal Transduction;NGF-independant TRKA activation;NTF4 activates NTRK2 (TRKB) signaling;Signaling by NTRK1 (TRKA);BDNF activates NTRK2 (TRKB) signaling;NTF3 activates NTRK2 (TRKB) signaling;Activated NTRK2 signals through RAS;Activated NTRK2 signals through PLCG1;Activated NTRK2 signals through FYN;Activated NTRK2 signals through CDK5;Signaling by NTRK2 (TRKB);Signaling by NTRKs;BDNF;SHP2 signaling;Posttranslational regulation of adherens junction stability and dissassembly;Activated NTRK2 signals through FRS2 and FRS3;Signaling by Receptor Tyrosine Kinases;Neurotrophic factor-mediated Trk receptor signaling (Consensus)

Recessive Scores

• pRec: 0.478

Intolerance Scores

• loftool: 0.0200
• rvis_EVS: -0.49
• rvis_percentile_EVS: 22.65

Haploinsufficiency Scores

• pHI: 0.419
• hipred: Y
• hipred_score: 0.853
• ghis: 0.529

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: Ntrk2
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; 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); liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); skeleton phenotype; hearing/vestibular/ear 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); vision/eye 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)

Zebrafish Information Network

• Gene name: ntrk2b
• Affected structure: posterior lateral line
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: vasculogenesis;neuron migration;positive regulation of protein phosphorylation;transmembrane receptor protein tyrosine kinase signaling pathway;activation of phospholipase C activity;nervous system development;learning;circadian rhythm;feeding behavior;positive regulation of cell population proliferation;positive regulation of gene expression;positive regulation of neuron projection development;glutamate secretion;positive regulation of phosphatidylinositol 3-kinase signaling;peptidyl-tyrosine phosphorylation;neuronal action potential propagation;central nervous system neuron development;cerebral cortex development;myelination in peripheral nervous system;neuron differentiation;brain-derived neurotrophic factor receptor signaling pathway;positive regulation of peptidyl-serine phosphorylation;mechanoreceptor differentiation;regulation of GTPase activity;regulation of MAPK cascade;positive regulation of MAPK cascade;negative regulation of neuron apoptotic process;retinal rod cell development;protein autophosphorylation;neurotrophin TRK receptor signaling pathway;oligodendrocyte differentiation;peripheral nervous system neuron development;positive regulation of axonogenesis;regulation of protein kinase B signaling;positive regulation of synapse assembly;retina development in camera-type eye;long-term synaptic potentiation;positive regulation of ERK1 and ERK2 cascade;cellular response to amino acid stimulus;trans-synaptic signaling by BDNF, modulating synaptic transmission;trans-synaptic signaling by neuropeptide, modulating synaptic transmission;positive regulation of non-membrane spanning protein tyrosine kinase activity;cellular response to nerve growth factor stimulus;cellular response to brain-derived neurotrophic factor stimulus;negative regulation of anoikis
• Cellular component: Golgi membrane;early endosome;cytosol;plasma membrane;integral component of plasma membrane;postsynaptic density;axon;dendrite;early endosome membrane;terminal bouton;dendritic spine;receptor complex;axon terminus;perinuclear region of cytoplasm
• Molecular function: protein tyrosine kinase activity;transmembrane receptor protein tyrosine kinase activity;neurotrophin receptor activity;protein binding;ATP binding;protein homodimerization activity;neurotrophin binding;brain-derived neurotrophic factor binding;brain-derived neurotrophic factor-activated receptor activity