HAVCR2

hepatitis A virus cellular receptor 2, the group of V-set domain containing

Basic information

Region (hg38): 5:157085421-157142869

Links

ENSG00000135077 ∙ NCBI:84868 ∙ OMIM:606652 ∙ HGNC:18437 ∙ Uniprot:Q8TDQ0 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
T-cell lymphoma, subcutaneous panniculitis-like	AR	Oncologic	Individuals have been described as being susceptible to form of T-cell non-Hodgkin lymphoma, and awareness may allow early surveillance, diagnosis, and management (immunosuppressive and chemotherapeutic treatment has been reported as effective); HSCT has been reported as curative	Oncologic	30374066; 30792187

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HAVCR2 gene.

• not provided (10 variants)
• Inborn genetic diseases (10 variants)
• Subcutaneous panniculitis-like T-cell lymphoma (5 variants)
• not specified (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HAVCR2 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				1		1
missense			7	4	2	13
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region						0
non coding			2		4	6
Total	0	0	10	5	6

Variants in HAVCR2

This is a list of pathogenic ClinVar variants found in the HAVCR2 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-157087114-A-G			Likely benign (Jul 01, 2022)
5-157087175-T-A		not specified	Uncertain significance (Mar 21, 2023)
5-157087178-G-A		HAVCR2-related disorder	Benign (Jan 01, 2024)
5-157087198-G-A			Likely benign (Apr 01, 2024)
5-157087232-C-T			Likely benign (May 01, 2022)
5-157087233-G-A		not specified	Uncertain significance (Apr 03, 2023)
5-157087304-T-C			Benign (Jul 16, 2018)
5-157095359-C-G		HAVCR2-related disorder	Likely benign (Jul 30, 2023)
5-157095368-A-G		not specified	Uncertain significance (Oct 16, 2023)
5-157095432-G-A		not specified	Uncertain significance (Sep 26, 2023)
5-157095460-C-T		Subcutaneous panniculitis-like T-cell lymphoma	Uncertain significance (Oct 30, 2023)
5-157098864-A-T		not specified	Uncertain significance (Mar 24, 2023)
5-157098865-T-C		not specified	Uncertain significance (Aug 12, 2021)
5-157098868-A-G		HAVCR2-related disorder	Benign (Oct 28, 2019)
5-157098871-T-A		not specified	Uncertain significance (Mar 06, 2023)
5-157098909-AAGAG-A		HAVCR2-related disorder	Benign/Likely benign (Mar 01, 2022)
5-157098909-A-AAG		HAVCR2-related disorder	Likely benign (May 23, 2019)
5-157098909-A-AAGAG		HAVCR2-related disorder	Likely benign (Jul 12, 2019)
5-157104550-C-T		not specified	Benign (Jan 24, 2024)
5-157104725-C-A		Subcutaneous panniculitis-like T-cell lymphoma • not specified	Benign (Jan 24, 2024)
5-157104726-G-A		not specified	Uncertain significance (Nov 09, 2023)
5-157104854-A-G		not specified	Benign (Jan 24, 2024)
5-157106636-T-C		not specified	Uncertain significance (Aug 02, 2021)
5-157106672-T-G		not specified	Likely benign (Dec 14, 2021)
5-157106689-C-T		Subcutaneous panniculitis-like T-cell lymphoma	Uncertain significance (-)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HAVCR2	protein_coding	protein_coding	ENST00000307851	7	57038

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0387	0.933	125672	0	3	125675	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.635	147	170	0.863	0.00000927	1925
Missense in Polyphen		25	39.508	0.63279		455
Synonymous	0.401	64	68.2	0.938	0.00000381	613
Loss of Function	1.89	4	10.7	0.375	4.49e-7	139

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000283	0.0000264
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Cell surface receptor implicated in modulating innate and adaptive immune responses. Generally accepted to have an inhibiting function. Reports on stimulating functions suggest that the activity may be influenced by the cellular context and/or the respective ligand (PubMed:24825777). Regulates macrophage activation (PubMed:11823861). Inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and alloimmune responses and promotes immunological tolerance (PubMed:14556005). In CD8+ cells attenuates TCR-induced signaling, specifically by blocking NF- kappaB and NFAT promoter activities resulting in the loss of IL-2 secretion. The function may implicate its association with LCK proposed to impair phosphorylation of TCR subunits, and/or LGALS9- dependent recruitment of PTPRC to the immunological synapse (PubMed:24337741, PubMed:26492563). In contrast, shown to activate TCR-induced signaling in T-cells probably implicating ZAP70, LCP2, LCK and FYN (By similarity). Expressed on Treg cells can inhibit Th17 cell responses (PubMed:24838857). Receptor for LGALS9 (PubMed:16286920, PubMed:24337741). Binding to LGALS9 is believed to result in suppression of T-cell responses; the resulting apoptosis of antigen-specific cells may implicate HAVCR2 phosphorylation and disruption of its association with BAG6. Binding to LGALS9 is proposed to be involved in innate immune response to intracellular pathogens. Expressed on Th1 cells interacts with LGALS9 expressed on Mycobacterium tuberculosis- infected macrophages to stimulate antibactericidal activity including IL-1 beta secretion and to restrict intracellular bacterial growth (By similarity). However, the function as receptor for LGALS9 has been challenged (PubMed:23555261). Also reported to enhance CD8+ T-cell responses to an acute infection such as by Listeria monocytogenes (By similarity). Receptor for phosphatidylserine (PtSer); PtSer-binding is calcium-dependent. May recognize PtSer on apoptotic cells leading to their phagocytosis. Mediates the engulfment of apoptotic cells by dendritic cells. Expressed on T-cells, promotes conjugation but not engulfment of apoptotic cells. Expressed on dendritic cells (DCs) positively regulates innate immune response and in synergy with Toll-like receptors promotes secretion of TNF-alpha. In tumor-imfiltrating DCs suppresses nucleic acid-mediated innate immune repsonse by interaction with HMGB1 and interfering with nucleic acid-sensing and trafficking of nucleid acids to endosomes (By similarity). Expressed on natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma production in response to LGALS9 (PubMed:22323453). In contrast, shown to suppress NK cell-mediated cytotoxicity (PubMed:22383801). Negatively regulates NK cell function in LPS-induced endotoxic shock (By similarity). {ECO:0000250|UniProtKB:Q8VIM0, ECO:0000269|PubMed:11823861, ECO:0000269|PubMed:14556005, ECO:0000269|PubMed:16286920, ECO:0000269|PubMed:22323453, ECO:0000269|PubMed:23555261, ECO:0000269|PubMed:24838857, ECO:0000269|PubMed:26492563, ECO:0000305|PubMed:24825777}.
• Disease: DISEASE: Note=May be involved in T-cell exhaustion associated with chronic viral infections such as with human immunodeficiency virus (HIV) and hepatitic C virus (HCV). {ECO:0000269|PubMed:19001139, ECO:0000269|PubMed:19587053}.
• Pathway: Ebola Virus Pathway on Host;Ebola Virus Pathway on Host;Signaling by Interleukins;Cytokine Signaling in Immune system;Immune System;Interleukin-2 family signaling (Consensus)

Intolerance Scores

• loftool: 0.713
• rvis_EVS: 0.97
• rvis_percentile_EVS: 90.34

Haploinsufficiency Scores

• pHI: 0.0682
• hipred: N
• hipred_score: 0.174
• ghis: 0.402

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.331

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Havcr2
• Phenotype: growth/size/body region phenotype; cellular phenotype; hematopoietic system 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); immune system phenotype

Gene ontology

• Biological process: adaptive immune response;macrophage activation involved in immune response;natural killer cell tolerance induction;regulation of tolerance induction dependent upon immune response;negative regulation of T-helper 1 type immune response;negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target;regulation of transcription by RNA polymerase II;inflammatory response;negative regulation of gene expression;negative regulation of myeloid dendritic cell activation;negative regulation of NF-kappaB transcription factor activity;negative regulation of interferon-alpha production;negative regulation of interferon-gamma production;negative regulation of interleukin-2 production;negative regulation of interleukin-3 production;negative regulation of interleukin-6 production;negative regulation of tumor necrosis factor production;positive regulation of chemokine production;positive regulation of interferon-gamma production;positive regulation of interleukin-1 production;positive regulation of interleukin-4 production;negative regulation of natural killer cell activation;toll-like receptor 3 signaling pathway;toll-like receptor 7 signaling pathway;toll-like receptor 9 signaling pathway;positive regulation of T cell proliferation;negative regulation of T cell proliferation;positive regulation of macrophage activation;innate immune response;defense response to Gram-positive bacterium;maternal process involved in female pregnancy;positive regulation of ERK1 and ERK2 cascade;cellular response to lipopolysaccharide;negative regulation of granulocyte colony-stimulating factor production;negative regulation of defense response to bacterium;positive regulation of defense response to bacterium;positive regulation of NIK/NF-kappaB signaling;positive regulation of tumor necrosis factor secretion;negative regulation of immunological synapse formation;negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell
• Cellular component: immunological synapse;early endosome;cell surface;integral component of membrane;mediator complex;cell junction
• Molecular function: protein binding;metal ion binding