STAT2

protein-coding

signal transducer and activator of transcription 2, the group of SH2 domain containing

Gene summary

The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. In response to interferon (IFN), this protein forms a complex with STAT1 and IFN regulatory factor family protein p48 (ISGF3G), in which this protein acts as a transactivator, but lacks the ability to bind DNA directly. The protein mediates innate antiviral activity. Mutations in this gene result in Immunodeficiency 44. [provided by RefSeq, Aug 2020]

MANE transcript

NM_005419.4

Inheritance

ClinVar variants

P:35U:241B:153

Top phenotype

Immunodeficiency 44; Pseudo-TORCH syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr12:56,341,597-56,360,203

External References & Databases

Ensembl (ENSG00000170581)

Transcript & Mutation Effects

hg38 • Region Span ~18.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

primary immunodeficiency with post-measles-mumps-rubella vaccine viral infectionSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014715

Submitter: Orphanet

primary immunodeficiency with post-measles-mumps-rubella vaccine viral infectionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014715

Submitter: Labcorp Genetics (formerly Invitae)

primary immunodeficiency with post-measles-mumps-rubella vaccine viral infectionLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014715

Submitter: G2P

primary immunodeficiency with post-measles-mumps-rubella vaccine viral infectionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014715

Submitter: PanelApp Australia

pseudo-TORCH syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030044

Submitter: Labcorp Genetics (formerly Invitae)

pseudo-TORCH syndrome 3LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030044

Submitter: G2P

Clinical Genomic Database (CGD)

Immunodeficiency 44; Pseudo-TORCH syndrome 3AR

Manifestation: Allergy/Immunology/Infectious; Biochemical; Renal

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals with both conditions can demonstrate infection susceptibility, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; In Immunodeficiency 44, adverse reactions to vaccinations have been reported, and awareness may help prevent morbidity; In Pseudo-Torch syndrome 3, the use of immunologic medical treatments (eg, dexamethasone, ruxolitinib) has been described as showing some benefit; HSCT has been described in Pseudo-Torch syndrome 3

Refs: 23391734; 26122121; 31836668; 32092142

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to STAT2 variants in ClinVar

7 Conditions Cataloged

Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infectionTotal: 515

not specifiedTotal: 68

Inborn genetic diseasesTotal: 63

not providedTotal: 57

STAT2-related disorderTotal: 15

Pseudo-TORCH syndrome 3Total: 7

Susceptibility to severe COVID-19Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005419.4. 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			8 clinvar	138 clinvar	2 clinvar	148
missense	2 clinvar	1 clinvar	224 clinvar	12 clinvar	1 clinvar	240
nonsense	10 clinvar	2 clinvar	2 clinvar			14
start loss						0
frameshift	13 clinvar	1 clinvar				14
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	7 clinvar			13
Total	27	8	241	150	3	429

Highest pathogenic variant AF is 0.000014364927

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005419.4	RefSeq	NP_005410.1	23	MANE Select
ENST00000314128.9	Ensembl	ENSP00000315768.4	23	MANE Select
NM_001385110.1	RefSeq	NP_001372039.1	22	Standard
NM_001385111.1	RefSeq	NP_001372040.1	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)
Chemokine signaling pathway - Homo sapiens (human)
Necroptosis - Homo sapiens (human)

Biological Process

regulation of protein phosphorylation
regulation of transcription by RNA polymerase II
JAK-STAT cascade
viral process
cytokine-mediated signaling pathway

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
protein binding
identical protein binding
ubiquitin-like protein ligase binding

Cellular Component

nucleoplasm
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000314128
Coding exons: 23
Length: 18559
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125748
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.60	299	455	0.658	0.0000248	5528
Missense (PolyPhen)		87	153.2	0.56788		1966
Synonymous	1.30	160	182	0.877	0.00000936	1658
Loss of Function	5.65	11	57.0	0.193	0.00000310	593

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Signal transducer and activator of transcription that mediates signaling by type I IFNs (IFN-alpha and IFN-beta). Following type I IFN binding to cell surface receptors, Jak kinases (TYK2 and JAK1) are activated, leading to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize, associate with IRF9/ISGF3G to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of interferon stimulated genes, which drive the cell in an antiviral state (PubMed:9020188, PubMed:23391734). Acts as a regulator of mitochondrial fission by modulating the phosphorylation of DNM1L at 'Ser-616' and 'Ser-637' which activate and inactivate the GTPase activity of DNM1L respectively (PubMed:26122121). {ECO:0000269|PubMed:23391734, ECO:0000269|PubMed:26122121, ECO:0000269|PubMed:9020188}.;
Disease: DISEASE: Immunodeficiency 44 (IMD44) [MIM:616636]: An autosomal recessive disorder characterized by increased susceptibility to viral infection, resulting in some patients in encephalopathy and infection-associated neurologic decompensation. {ECO:0000269|PubMed:23391734, ECO:0000269|PubMed:26122121}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.357

Intolerance Scores

LoFtool: 0.154
RVIS EVS: -0.73
RVIS percentile EVS: 14.14

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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