TNK2

protein-coding

tyrosine kinase non receptor 2, the group of MicroRNA protein coding host genes|TNK family tyrosine kinases

Gene summary

This gene encodes a tyrosine kinase that binds Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs. This binding is mediated by a unique sequence of 47 amino acids C-terminal to an SH3 domain. The protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. Several alternatively spliced transcript variants have been identified from this gene, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001382273.1

Inheritance

ClinVar variants

P:1U:312B:125

Top phenotype

infantile-onset mesial temporal lobe epilepsy with severe cognitive regression

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr3:195,863,364-195,911,945

External References & Databases

Ensembl (ENSG00000061938)

Transcript & Mutation Effects

hg38 • Region Span ~48.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

infantile-onset mesial temporal lobe epilepsy with severe cognitive regressionSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018314

Submitter: Orphanet

genetic generalized epilepsyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100575

Submitter: PanelApp Australia

epilepsyNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0005027

Submitter: ClinGen

*TNK2* was first reported in relation to autosomal recessive epilepsy in 2013 (Hitomi et al., PMID: 23686771). Four years later, Mao et al. (PMID: 27977884) reported four variants (missense or nonsense) in two families with autosomal recessive infantile spasms. However, the authors of the original report (PMID: 23686771) responded with a retraction of their publication after it became clear that the variant was too frequent in the general population to be the cause of the disease (2,790/1,601,154 alleles and 25 homozygotes in gnomAD v4.1). No further credible genetic evidence for the association of *TNK2* with epilepsy has been reported. In addition, *TNK2* is relatively tolerant to both missense and loss of function variants according to gnomADv4.1. In summary, the evidence supporting the relationship between *TNK2* and autosomal recessive epilepsy has been refuted and no valid evidence remains to support the claim. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date July 21, 2026 (SOP Version 12).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TNK2 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 269

not specifiedTotal: 254

TNK2-related disorderTotal: 22

Parkinson diseaseTotal: 4

Abnormality of neuronal migrationTotal: 2

Epileptic encephalopathyTotal: 1

Autosomal recessive infantile epilepsyTotal: 1

TNK2-associated Epilepsy syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001382273.1. 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			5 clinvar	75 clinvar	24 clinvar	104
missense	1 clinvar		295 clinvar	20 clinvar	6 clinvar	322
nonsense			2 clinvar			2
start loss						0
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	1	0	312	95	30	438

Highest pathogenic variant AF is 0.0000037188868

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 103 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001382273.1	RefSeq	NP_001369202.1	15	MANE Select
ENST00000672887.2	Ensembl	ENSP00000499899.1	15	MANE Select
NM_001010938.2	RefSeq	NP_001010938.2	15	Standard
NM_001308046.2	RefSeq	NP_001294975.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Focal Adhesion
Oxidative Damage
EGF-EGFR Signaling Pathway
G13 Signaling Pathway
EGFR1

Biological Process

endocytosis
cell surface receptor signaling pathway
small GTPase mediated signal transduction
phosphorylation
cell differentiation

Molecular Function

protein serine/threonine kinase activity
protein serine/threonine/tyrosine kinase activity
protein tyrosine kinase activity
non-membrane spanning protein tyrosine kinase activity
GTPase inhibitor activity

Cellular Component

nucleus
cytoplasm
endosome
plasma membrane
clathrin-coated pit

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000381916
Coding exons: 15
Length: 48582
Individuals with no LoFs: 125678
Homozygous LoFs: 0
Heterozygous LoFs: 70
Defined: 125748
p: 0.000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.202	710	695	1.02	0.0000479	6863
Missense (PolyPhen)		225	259.45	0.86722		2555
Synonymous	-4.89	416	307	1.36	0.0000218	2358
Loss of Function	2.61	25	43.6	0.574	0.00000229	448

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00052	0.00049	rare
Latino/Admixed American	0.00024	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00016	rare
Finnish	0.000096	0.000092	rare
European (Non-Finnish)	0.00034	0.00033	rare
South Asian	0.00033	0.00033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Non-receptor tyrosine-protein and serine/threonine- protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr- 287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR. Phosphorylates WASP (PubMed:20110370). {ECO:0000269|PubMed:10652228, ECO:0000269|PubMed:11278436, ECO:0000269|PubMed:16247015, ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:17038317, ECO:0000269|PubMed:18262180, ECO:0000269|PubMed:18435854, ECO:0000269|PubMed:19815557, ECO:0000269|PubMed:20110370, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20383201}.;

Recessive Scores

pRec: 0.423

Intolerance Scores

LoFtool: 0.779
RVIS EVS: -0.72
RVIS percentile EVS: 14.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.990

Gene Damage Prediction

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