TAP2

protein-coding

transporter 2, ATP binding cassette subfamily B member, the group of ATP binding cassette subfamily B

Gene summary

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. This gene is located 7 kb telomeric to gene family member ABCB2. The protein encoded by this gene is involved in antigen presentation. This protein forms a heterodimer with ABCB2 in order to transport peptides from the cytoplasm to the endoplasmic reticulum. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Alternative splicing of this gene produces products which differ in peptide selectivity and level of restoration of surface expression of MHC class I molecules. [provided by RefSeq, Feb 2014]

Previous symbols:

ABCB3

MANE transcript

NM_001290043.2

Inheritance

ClinVar variants

P:27U:229B:143

Top phenotype

MHC class I deficiency 2

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr6:32,821,833-32,838,739

External References & Databases

Ensembl (ENSG00000204267)

Transcript & Mutation Effects

hg38 • Region Span ~16.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

MHC class I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011476

Submitter: Orphanet

MHC class I deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011476

Submitter: Ambry Genetics

MHC class I deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011476

Submitter: Labcorp Genetics (formerly Invitae)

MHC class I deficiency 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0971006

Submitter: PanelApp Australia

MHC class I deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011476

Submitter: ClinGen

TAP2 was first reported in relation to autosomal recessive major histocompatibility complex (MHC) class I deficiency in 1994 (de la Salle et al., PMID: 7517574). This condition is characterized by chronic bacterial infections and/or cutaneous granulomatous lesions. Bacterial infections may impact the upper and lower respiratory tract, causing sinusitis, otitis media, bronchitis, pneumonia, and bronchiectasis. Some individuals are asymptomatic. (PMID: 12067308, 36227411) The immunophenotype of TAP2-related MHC class I deficiency has been reported as normal total CD8+ T cell counts but decreased naïve CD8+ T cell counts and increased alpha-beta T cells. (PMID: 36227411) Heterozygous carriers are apparently unaffected. (PMID: 10560675, 12067308, 36227411) Six variants (nonsense, frameshift, and splice site) that have been reported in six probands in six publications (PMIDs: 7517574, 10560675, 12067308, 23662797, 20083708, 36227411) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by protein interaction, functional alteration in patient cells, a rescue study, and mouse models. (PMIDs: 9651323, 10560675, 19721454, 27861817, 7517574) The TAP complex is made up of TAP1 and TAP2. (PMID: 9651323) We have previously established TAP1 as definitively associated with MHC class I deficiency. TAP2 deficient patient cells have deficient MHC class I surface expression (PMID: 7517574), and expression of wild-type TAP2 in patient cells restores that expression (PMID: 10560675) Animal models also recapitulate the phenotype seen in humans with absent MHC class I expression. (PMID: 19721454, 27861817) In summary, there is definitive evidence supporting the relationship between TAP2 and autosomal recessive MHC class I deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date October 19, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

MHC class I deficiency 2AR

Manifestation: Allergy/Immunology/Infectious; Pulmonary

Intervention: Allergy/Immunology/Infectious; Pulmonary

Rationale: Individuals may manifest with frequent and severe infections (including early-onset severe bacterial infections), and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; For pulmonary manifestations, treatment recommendations analogous to those in individuals cystic fibrosis have been recommended; Immunosuppressive therapy may be contraindicated

Comments: The condition has been reported as possibly related to increased risk of malignancy as well as infectious manifestations

Refs: 7517574; 10074495; 10931128; 12644316; 17879436; 17879452; 20083708; 36229627

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TAP2 variants in ClinVar

8 Conditions Cataloged

MHC class I deficiencyTotal: 405

Inborn genetic diseasesTotal: 79

not specifiedTotal: 46

not providedTotal: 37

TAP2-related disorderTotal: 18

MHC class I deficiency 2Total: 4

MHC class I deficiency 1Total: 3

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001290043.2. 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			4 clinvar	120 clinvar	5 clinvar	129
missense			214 clinvar	16 clinvar	2 clinvar	232
nonsense	9 clinvar	1 clinvar	3 clinvar			13
start loss			2 clinvar			2
frameshift	9 clinvar	2 clinvar				11
splice donor/acceptor (+/-2bp)		6 clinvar	6 clinvar			12
Total	18	9	229	136	7	399

Highest pathogenic variant AF is 0.000022320073

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001290043.2	RefSeq	NP_001276972.1	11	MANE Select
ENST00000374897.4	Ensembl	ENSP00000364032.3	11	MANE Select
NM_018833.3	RefSeq	NP_061313.2	11	Standard
ENST00000652259.1	Ensembl	ENSP00000498827.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Antigen processing and presentation - Homo sapiens (human)
Primary immunodeficiency - Homo sapiens (human)
Phagosome - Homo sapiens (human)
ABC transporters - Homo sapiens (human)
Herpes simplex infection - Homo sapiens (human)

Biological Process

adaptive immune response
antigen processing and presentation of peptide antigen via MHC class I
antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent
antigen processing and presentation of endogenous peptide antigen via MHC class Ib via ER pathway, TAP-dependent
protein transport

Molecular Function

transporter activity
protein binding
ATP binding
peptide antigen-transporting ATPase activity
MHC class Ib protein binding

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
membrane
integral component of membrane
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374899
Coding exons: 11
Length: 16948
Individuals with no LoFs: 125686
Homozygous LoFs: 0
Heterozygous LoFs: 62
Defined: 125748
p: 0.000247

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.39	281	355	0.792	0.0000219	4124
Missense (PolyPhen)		88	115.89	0.75933		1372
Synonymous	0.581	148	157	0.941	0.00000944	1438
Loss of Function	2.51	17	32.4	0.525	0.00000205	322

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00096	0.00095	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00018	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00017	0.00016	rare
South Asian	0.00016	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the transport of antigens from the cytoplasm to the endoplasmic reticulum for association with MHC class I molecules. Also acts as a molecular scaffold for the final stage of MHC class I folding, namely the binding of peptide. Nascent MHC class I molecules associate with TAP via tapasin. Inhibited by the covalent attachment of herpes simplex virus ICP47 protein, which blocks the peptide-binding site of TAP. Inhibited by human cytomegalovirus US6 glycoprotein, which binds to the lumenal side of the TAP complex and inhibits peptide translocation by specifically blocking ATP-binding to TAP1 and prevents the conformational rearrangement of TAP induced by peptide binding. Inhibited by human adenovirus E3-19K glycoprotein, which binds the TAP complex and acts as a tapasin inhibitor, preventing MHC class I/TAP association.;
Disease: DISEASE: Bare lymphocyte syndrome 1 (BLS1) [MIM:604571]: A HLA class I deficiency. Contrary to bare lymphocyte syndromes type 2 and type 3, which are characterized by early-onset severe combined immunodeficiency, class I antigen deficiencies are not accompanied by particular pathologic manifestations during the first years of life. Systemic infections have not been described. Chronic bacterial infections, often beginning in the first decade of life, are restricted to the respiratory tract. {ECO:0000269|PubMed:7517574}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.487

Intolerance Scores

LoFtool: 0.0606
RVIS EVS: 1.53
RVIS percentile EVS: 95.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.799

Gene Damage Prediction

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