TYK2

protein-coding

tyrosine kinase 2, the group of FERM domain containing|Jak family tyrosine kinases

Gene summary

This gene encodes a member of the tyrosine kinase and, more specifically, the Janus kinases (JAKs) protein families. This protein associates with the cytoplasmic domain of type I and type II cytokine receptors and promulgate cytokine signals by phosphorylating receptor subunits. It is also a component of both the type I and type III interferon signaling pathways. As such, it may play a role in anti-viral immunity. A mutation in this gene has been associated with Immunodeficiency 35. [provided by RefSeq, Sep 2020]

MANE transcript

NM_003331.5

Inheritance

ClinVar variants

P:49U:475B:303

Top phenotype

Immunodeficiency 35

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr19:10,350,528-10,380,608

External References & Databases

Ensembl (ENSG00000105397)

Transcript & Mutation Effects

hg38 • Region Span ~30.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012682

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 35STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012682

Submitter: PanelApp Australia

immunodeficiency 35SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012682

Submitter: Orphanet

Clinical Genomic Database (CGD)

Immunodeficiency 35AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 17088085; 17521577; 18270328; 26304966

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TYK2 variants in ClinVar

7 Conditions Cataloged

Immunodeficiency 35Total: 905

not providedTotal: 149

Inborn genetic diseasesTotal: 133

not specifiedTotal: 105

TYK2-related disorderTotal: 31

ImmunodeficiencyTotal: 2

Recurrent skin infectionsTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003331.5. 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			15 clinvar	263 clinvar	6 clinvar	284
missense	2 clinvar	1 clinvar	452 clinvar	30 clinvar	4 clinvar	489
nonsense	11 clinvar	3 clinvar	1 clinvar			15
start loss						0
frameshift	10 clinvar	6 clinvar				16
splice donor/acceptor (+/-2bp)		16 clinvar	7 clinvar			23
Total	23	26	475	293	10	827

Highest pathogenic variant AF is 0.00019908336

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 84 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003331.5	RefSeq	NP_003322.3	23	MANE Select
ENST00000525621.6	Ensembl	ENSP00000431885.1	23	MANE Select
NM_001385197.1	RefSeq	NP_001372126.1	22	Standard
NM_001385198.1	RefSeq	NP_001372127.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
Jak-STAT signaling pathway - Homo sapiens (human)
Influenza A - Homo sapiens (human)
Necroptosis - Homo sapiens (human)
NOD-like receptor signaling pathway - Homo sapiens (human)

Biological Process

protein phosphorylation
peptidyl-tyrosine phosphorylation
cytokine-mediated signaling pathway
intracellular signal transduction
interleukin-12-mediated signaling pathway

Molecular Function

protein tyrosine kinase activity
non-membrane spanning protein tyrosine kinase activity
growth hormone receptor binding
protein binding
ATP binding

Cellular Component

nucleus
cytoplasm
cytosol
cytoskeleton
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000525621
Coding exons: 23
Length: 30144
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.59	620	742	0.836	0.0000506	7674
Missense (PolyPhen)		156	247.92	0.62924		2810
Synonymous	0.818	297	315	0.941	0.0000221	2412
Loss of Function	4.24	23	57.7	0.398	0.00000309	618

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0012	0.0012	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain. {ECO:0000269|PubMed:7526154}.;
Disease: DISEASE: Immunodeficiency 35 (IMD35) [MIM:611521]: A primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE. {ECO:0000269|PubMed:17088085}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.671

Intolerance Scores

LoFtool: 0.209
RVIS EVS: -0.5
RVIS percentile EVS: 21.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

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