ALK

ALK receptor tyrosine kinase, the group of Receptor tyrosine kinases|CD molecules

Basic information

Region (hg38): 2:29192773-29921586

Links

ENSG00000171094 ∙ NCBI:238 ∙ OMIM:105590 ∙ HGNC:427 ∙ Uniprot:Q9UM73 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neuroblastoma, susceptibility to, 3 (Strong), mode of inheritance: AD
• neuroblastoma, susceptibility to, 3 (Strong), mode of inheritance: AD
• neuroblastoma, susceptibility to, 3 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neuroblastoma, susceptibility to, 3	AD	Oncologic	Surveillance (eg, with frequent abdominal ultrasound and urinary catecholamine testing) and awareness of cancer risk may allow early diagnosis and treatment of tumors, which may reduce morbidity and mortality	Oncologic	18923523; 18724359; 18242317; 20301782

ClinVar

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

• Neuroblastoma, susceptibility to, 3 (3626 variants)
• Hereditary cancer-predisposing syndrome (1898 variants)
• not provided (398 variants)
• not specified (97 variants)
• ALK-related condition (22 variants)
• Ovarian cancer (15 variants)
• Familial isolated pituitary adenoma (12 variants)
• Inborn genetic diseases (9 variants)
• Neuroblastoma Susceptibility (7 variants)
• Squamous cell lung carcinoma (7 variants)
• Neuroblastoma (6 variants)
• Non-small cell lung carcinoma (2 variants)
• Lung adenocarcinoma (2 variants)
• Neoplasm of brain (2 variants)
• Diffuse midline glioma, H3 K27-altered (1 variants)
• Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (1 variants)
• Lung cancer (1 variants)
• Rhabdomyosarcoma (1 variants)
• Multiple endocrine neoplasia, type 2a (1 variants)
• Breast neoplasm (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ALK 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			22	1071	15	1108
missense	2	3	2172	24	12	2213
nonsense			57			57
start loss			2			2
frameshift			74			74
inframe indel			29	1		30
splice donor/acceptor (+/-2bp)			50			50
splice region			98	120	4	222
non coding			43	375	112	530
Total	2	3	2449	1471	139

Highest pathogenic variant AF is 0.0000131

Variants in ALK

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

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

Position	Type	Phenotype	Significance	ClinVar
2-29192809-C-T		Neuroblastoma Susceptibility	Uncertain significance (Jun 14, 2016)
2-29192817-T-G		Neuroblastoma, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
2-29192821-A-G		Neuroblastoma, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
2-29192926-G-A		Neuroblastoma, susceptibility to, 3	Benign (Jan 12, 2018)
2-29192978-C-T		Neuroblastoma, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
2-29193035-A-G		Neuroblastoma, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
2-29193039-G-A		Neuroblastoma, susceptibility to, 3	Uncertain significance (Jan 13, 2018)
2-29193113-G-A		Neuroblastoma, susceptibility to, 3	Benign (Jun 23, 2018)
2-29193158-C-CCATT		Neuroblastoma Susceptibility	Uncertain significance (Jun 14, 2016)
2-29193159-C-CATTG		Neuroblastoma Susceptibility	Benign (Jun 14, 2018)
2-29193161-T-C		Neuroblastoma, susceptibility to, 3	Benign/Likely benign (Dec 24, 2018)
2-29193171-C-G		Neuroblastoma, susceptibility to, 3	Benign (Jun 23, 2018)
2-29193179-C-T		Neuroblastoma, susceptibility to, 3	Benign (Jan 12, 2018)
2-29193211-TGTGCGACCGAGCTCAG-T		Neuroblastoma, susceptibility to, 3	Uncertain significance (Apr 28, 2023)
2-29193219-CGAGCTCA-C		Neuroblastoma, susceptibility to, 3	Uncertain significance (Dec 28, 2023)
2-29193225-C-T		Neuroblastoma, susceptibility to, 3 • Hereditary cancer-predisposing syndrome	Likely benign (Oct 04, 2023)
2-29193226-A-G		Neuroblastoma, susceptibility to, 3	Uncertain significance (Oct 01, 2021)
2-29193227-G-A		Neuroblastoma, susceptibility to, 3	Likely benign (Jun 09, 2021)
2-29193227-G-C		Neuroblastoma, susceptibility to, 3	Uncertain significance (Dec 28, 2021)
2-29193228-G-A		Neuroblastoma, susceptibility to, 3	Uncertain significance (Nov 28, 2023)
2-29193229-G-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Nov 11, 2023)
2-29193230-C-T		Neuroblastoma, susceptibility to, 3 • Hereditary cancer-predisposing syndrome	Likely benign (Dec 03, 2022)
2-29193231-C-A		Hereditary cancer-predisposing syndrome • Neuroblastoma, susceptibility to, 3	Uncertain significance (Oct 28, 2023)
2-29193232-C-T		Neuroblastoma, susceptibility to, 3 • Hereditary cancer-predisposing syndrome	Uncertain significance (Jan 22, 2023)
2-29193232-C-CAGGCTGGTTCATGCTATTCTTGCTTTT		Neuroblastoma, susceptibility to, 3	Uncertain significance (Apr 06, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ALK	protein_coding	protein_coding	ENST00000389048	29	728793

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000323	1.00	125341	0	407	125748	0.00162

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0103	919	920	0.999	0.0000535	10449
Missense in Polyphen		319	390.09	0.81777		4515
Synonymous	-2.65	449	383	1.17	0.0000244	3305
Loss of Function	5.56	25	78.0	0.321	0.00000406	854

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00620	0.00616
Ashkenazi Jewish	0.00314	0.00288
East Asian	0.00148	0.00136
Finnish	0.00159	0.00153
European (Non-Finnish)	0.00101	0.000950
Middle Eastern	0.00148	0.00136
South Asian	0.00142	0.00131
Other	0.00337	0.00294

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y- x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK. {ECO:0000269|PubMed:11121404, ECO:0000269|PubMed:11278720, ECO:0000269|PubMed:11387242, ECO:0000269|PubMed:11809760, ECO:0000269|PubMed:12107166, ECO:0000269|PubMed:12122009, ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:15908427, ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988}.
• Disease: DISEASE: Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas.; DISEASE: Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A.; DISEASE: Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17.; DISEASE: Neuroblastoma 3 (NBLST3) [MIM:613014]: A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system. {ECO:0000269|PubMed:18724359, ECO:0000269|PubMed:18923523, ECO:0000269|PubMed:18923525, ECO:0000269|PubMed:21242967}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.; DISEASE: Note=A chromosomal aberration involving ALK is found in one subject with colorectal cancer. Translocation t(2;2)(p23.1;p23.3). A 5 million base pair tandem duplication generates an in-frame WDCP-ALK gene fusion. {ECO:0000269|PubMed:22327622}.
• Pathway: Non-small cell lung cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Differentiation Pathway;MET in type 1 papillary renal cell carcinoma;Disease;Gene expression (Transcription);Generic Transcription Pathway;Interactions of Rev with host cellular proteins;Host Interactions of HIV factors;HIV Infection;RNA Polymerase II Transcription;Infectious disease;Nucleosome assembly;IL-7 signaling;Chromosome Maintenance;TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain;TP53 Regulates Transcription of Cell Cycle Genes;JAK STAT pathway and regulation;Deposition of new CENPA-containing nucleosomes at the centromere;EPO signaling;Transcriptional Regulation by TP53;TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation;Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors;Nuclear import of Rev protein;Cell Cycle;VEGF (Consensus)

Recessive Scores

• pRec: 0.419

Intolerance Scores

• loftool: 0.202
• rvis_EVS: -2.24
• rvis_percentile_EVS: 1.3

Haploinsufficiency Scores

• pHI: 0.215
• hipred: Y
• hipred_score: 0.575
• ghis: 0.423

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.802

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Alk
• 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; homeostasis/metabolism phenotype; vision/eye 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); reproductive system phenotype; neoplasm; pigmentation phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory 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: alk
• Affected structure: hindbrain
• Phenotype tag: abnormal
• Phenotype quality: apoptotic

Gene ontology

• Biological process: activation of MAPK activity;signal transduction;transmembrane receptor protein tyrosine kinase signaling pathway;cell population proliferation;phosphorylation;peptidyl-tyrosine phosphorylation;hippocampus development;adult behavior;swimming behavior;NIK/NF-kappaB signaling;regulation of cell population proliferation;regulation of apoptotic process;regulation of neuron differentiation;protein autophosphorylation;neuron development;positive regulation of NF-kappaB transcription factor activity;regulation of dopamine receptor signaling pathway;response to environmental enrichment
• Cellular component: plasma membrane;integral component of plasma membrane;protein-containing complex;receptor complex;extracellular exosome
• Molecular function: NF-kappaB-inducing kinase activity;protein tyrosine kinase activity;transmembrane receptor protein tyrosine kinase activity;protein binding;ATP binding;identical protein binding