F2

coagulation factor II, thrombin, the group of Gla domain containing|Complement system regulators and receptors|Receptor ligands

Basic information

Region (hg38): 11:46719196-46739506

Links

ENSG00000180210 ∙ NCBI:2147 ∙ OMIM:176930 ∙ HGNC:3535 ∙ Uniprot:P00734 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• thrombophilia due to thrombin defect (Strong), mode of inheritance: AD
• congenital prothrombin deficiency (Supportive), mode of inheritance: AR
• congenital prothrombin deficiency (Strong), mode of inheritance: AR
• congenital prothrombin deficiency (Strong), mode of inheritance: AR
• thrombophilia due to thrombin defect (Strong), mode of inheritance: AD
• thrombophilia due to thrombin defect (Definitive), mode of inheritance: AD
• congenital prothrombin deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Prothrombin deficiency, congenital; Thrombophilia due to thrombin defect	AD/AR	Hematologic; Pharmacogenomic	In individuals with Thrombophilia due to thrombin defect , as relates to the specific 20210G-A variant, variant carriers may benefit from preventive measures and/or other interventions when other risk factors are present or in symptomatic disease; In AR forms of disease (Prothrombin deficiency), surveillance and prompt treatment of bleeding diatheses may reduce morbidity; Precautions should be taken related to certain agents that may provoke/worsen bleeding risk	Hematologic	4489469; 7740448; 8916933; 9869612; 10233438; 10477778; 11734673; 10666427; 11167765; 11506076; 15534175; 19598065; 22716977
Variants in F2 may interact with variants in other genes, such as F5, to result in susceptibility to hematologic manifestations; Heterozygous variants associated with Prothrombin deficiency have been described as demonstrating increased bleeding tendency, such as post-dental or surgical bleeding

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the F2 gene.

• Congenital prothrombin deficiency (12 variants)
• Thrombophilia due to thrombin defect (1 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the F2 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			2	108		110
missense	5	7	45	5		62
nonsense	5	2				7
start loss						0
frameshift	2	1	1			4
inframe indel		1				1
splice donor/acceptor (+/-2bp)		1	1			2
splice region			4	15		19
non coding			5	73	22	100
Total	12	12	54	186	22

Highest pathogenic variant AF is 0.000197

Variants in F2

This is a list of pathogenic ClinVar variants found in the F2 region.

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

Position	Type	Phenotype	Significance	ClinVar
11-46719241-G-A		Congenital prothrombin deficiency	Likely benign (Jan 09, 2023)
11-46719248-C-T		Congenital prothrombin deficiency	Pathogenic (Jun 14, 2023)
11-46719254-T-C		Congenital prothrombin deficiency	Likely benign (Feb 08, 2023)
11-46719280-G-A		Thrombophilia due to thrombin defect • Congenital prothrombin deficiency	Conflicting classifications of pathogenicity (Jul 28, 2023)
11-46719304-C-T		Congenital prothrombin deficiency	Likely benign (Jan 18, 2024)
11-46719321-G-A		Thrombophilia due to thrombin defect • Congenital prothrombin deficiency • not specified	Benign/Likely benign (Jan 31, 2024)
11-46719324-T-C		Congenital prothrombin deficiency	Likely benign (Jul 19, 2023)
11-46719329-G-A		Congenital prothrombin deficiency	Likely benign (Jan 13, 2024)
11-46719329-G-T		Congenital prothrombin deficiency	Likely benign (Nov 24, 2023)
11-46719331-A-G		Congenital prothrombin deficiency	Likely benign (Nov 15, 2023)
11-46719682-A-AC		Congenital prothrombin deficiency	Benign (Aug 16, 2023)
11-46719684-C-A		Congenital prothrombin deficiency	Likely benign (Feb 01, 2023)
11-46719684-C-G		Congenital prothrombin deficiency	Likely benign (Nov 24, 2023)
11-46719688-C-T		Congenital prothrombin deficiency	Likely benign (Aug 07, 2023)
11-46719689-C-G		Congenital prothrombin deficiency	Likely benign (Oct 07, 2023)
11-46719689-C-T		Congenital prothrombin deficiency	Likely benign (Dec 05, 2022)
11-46719689-C-CA		Congenital prothrombin deficiency	Likely benign (Nov 10, 2023)
11-46719690-A-C		Congenital prothrombin deficiency	Likely benign (May 24, 2023)
11-46719690-A-G		Congenital prothrombin deficiency	Likely benign (Sep 10, 2023)
11-46719692-C-T		Congenital prothrombin deficiency	Likely benign (Jan 01, 2024)
11-46719693-G-A		Congenital prothrombin deficiency	Likely benign (Feb 09, 2023)
11-46719720-A-C			Uncertain significance (Jul 01, 2022)
11-46719725-C-T		Inborn genetic diseases	Uncertain significance (Dec 08, 2023)
11-46719726-G-A		Inborn genetic diseases	Uncertain significance (Mar 20, 2024)
11-46719727-G-A		Congenital prothrombin deficiency	Likely benign (Dec 26, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
F2	protein_coding	protein_coding	ENST00000311907	14	20327

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00111	0.999	125621	0	127	125748	0.000505

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.11	263	378	0.695	0.0000251	4041
Missense in Polyphen		71	151.31	0.46923		1594
Synonymous	0.713	143	154	0.927	0.0000107	1208
Loss of Function	3.74	12	36.3	0.331	0.00000208	373

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000254	0.000239
Ashkenazi Jewish	0.00	0.00
East Asian	0.000117	0.000109
Finnish	0.000560	0.000554
European (Non-Finnish)	0.000989	0.000923
Middle Eastern	0.000117	0.000109
South Asian	0.0000653	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing. {ECO:0000269|PubMed:2856554}.
• Disease: DISEASE: Factor II deficiency (FA2D) [MIM:613679]: A very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels. {ECO:0000269|PubMed:1349838, ECO:0000269|PubMed:1354985, ECO:0000269|PubMed:1421398, ECO:0000269|PubMed:14962227, ECO:0000269|PubMed:2719946, ECO:0000269|PubMed:3242619, ECO:0000269|PubMed:3567158, ECO:0000269|PubMed:3771562, ECO:0000269|PubMed:3801671, ECO:0000269|PubMed:6405779, ECO:0000269|PubMed:7792730, ECO:0000269|PubMed:7865694}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:15534175}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Thrombophilia due to thrombin defect (THPH1) [MIM:188050]: A multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. {ECO:0000269|PubMed:2825773}. Note=The disease is caused by mutations affecting the gene represented in this entry. A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis.; DISEASE: Pregnancy loss, recurrent, 2 (RPRGL2) [MIM:614390]: A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions. {ECO:0000269|PubMed:11506076}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Complement and coagulation cascades - Homo sapiens (human);Regulation of actin cytoskeleton - Homo sapiens (human);Neuroactive ligand-receptor interaction - Homo sapiens (human);Warfarin Pathway, Pharmacodynamics;Platelet Aggregation Inhibitor Pathway, Pharmacodynamics;Aminocaproic Acid Action Pathway;Tranexamic Acid Action Pathway;Urokinase Action Pathway;Reteplase Action Pathway;Streptokinase Action Pathway;Tenecteplase Action Pathway;Alteplase Action Pathway;Anistreplase Action Pathway;Aprotinin Action Pathway;Phenindione Action Pathway;Dicoumarol Action Pathway;Warfarin Action Pathway;Acenocoumarol Action Pathway;Vitamin K Metabolism;Coagulation ;Bivalirudin Action Pathway;Argatroban Action Pathway;Ardeparin Action Pathway;Heparin Action Pathway;Fondaparinux Action Pathway;Enoxaparin Action Pathway;Phenprocoumon Action Pathway;Dicumarol Action Pathway;Ximelagatran Action Pathway;Lepirudin Action Pathway;Selenium Micronutrient Network;Vitamin B12 Metabolism;Folate Metabolism;Blood Clotting Cascade;IL1 and megakaryocytes in obesity;Dengue-2 Interactions with Complement and Coagulation Cascades;Dengue-2 Interactions with Blood Clotting Cascade;Regulation of Actin Cytoskeleton;Complement and Coagulation Cascades;Signaling by GPCR;Signal Transduction;g-protein signaling through tubby proteins;aspirin blocks signaling pathway involved in platelet activation;corticosteroids and cardioprotection;cystic fibrosis transmembrane conductance regulator (cftr) and beta 2 adrenergic receptor (b2ar) pathway;ion channels and their functional role in vascular endothelium;activation of csk by camp-dependent protein kinase inhibits signaling through the t cell receptor;chrebp regulation by carbohydrates and camp;thrombin signaling and protease-activated receptors;fibrinolysis pathway;role of -arrestins in the activation and targeting of map kinases;intrinsic prothrombin activation pathway;activation of camp-dependent protein kinase pka;Post-translational protein modification;Metabolism of proteins;DroToll-like;Gamma-carboxylation of protein precursors;Removal of aminoterminal propeptides from gamma-carboxylated proteins;Gamma-carboxylation, transport, and amino-terminal cleavage of proteins;Gamma carboxylation, hypusine formation and arylsulfatase activation;Innate Immune System;Immune System;Peptide ligand-binding receptors;Class A/1 (Rhodopsin-like receptors);roles of arrestin dependent recruitment of src kinases in gpcr signaling;Thrombin signalling through proteinase activated receptors (PARs);GPCR ligand binding;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);Platelet Aggregation (Plug Formation);activation of pkc through g-protein coupled receptors;Platelet activation, signaling and aggregation;Intrinsic Pathway of Fibrin Clot Formation;Cell surface interactions at the vascular wall;Hemostasis;-arrestins in gpcr desensitization;transcriptional activation of dbpb from mrna;Common Pathway of Fibrin Clot Formation;Formation of Fibrin Clot (Clotting Cascade);Regulation of Complement cascade;Angiopoietin receptor Tie2-mediated signaling;Complement cascade;G alpha (q) signalling events;GPCR downstream signalling;PAR4-mediated thrombin signaling events;PAR1-mediated thrombin signaling events;FOXA2 and FOXA3 transcription factor networks;Syndecan-4-mediated signaling events;extrinsic prothrombin activation pathway (Consensus)

Recessive Scores

• pRec: 0.148

Intolerance Scores

• loftool: 0.125
• rvis_EVS: -0.71
• rvis_percentile_EVS: 14.57

Haploinsufficiency Scores

• pHI: 0.709
• hipred: Y
• hipred_score: 0.635
• ghis: 0.582

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.955

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: F2
• 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; homeostasis/metabolism 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); digestive/alimentary phenotype; reproductive 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); normal phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; skeleton phenotype; immune system phenotype

Gene ontology

• Biological process: positive regulation of protein phosphorylation;proteolysis;endoplasmic reticulum to Golgi vesicle-mediated transport;acute-phase response;cell surface receptor signaling pathway;G protein-coupled receptor signaling pathway;multicellular organism development;blood coagulation;blood coagulation, intrinsic pathway;positive regulation of cell population proliferation;regulation of cell shape;response to wounding;regulation of gene expression;regulation of signaling receptor activity;negative regulation of platelet activation;positive regulation of phosphatidylinositol 3-kinase signaling;platelet activation;regulation of blood coagulation;positive regulation of blood coagulation;positive regulation of cell growth;regulation of complement activation;positive regulation of collagen biosynthetic process;fibrinolysis;cellular protein metabolic process;negative regulation of proteolysis;positive regulation of JAK-STAT cascade;negative regulation of astrocyte differentiation;positive regulation of release of sequestered calcium ion into cytosol;regulation of cytosolic calcium ion concentration;cytolysis by host of symbiont cells;negative regulation of fibrinolysis;antimicrobial humoral immune response mediated by antimicrobial peptide;neutrophil mediated killing of gram-negative bacterium;positive regulation of lipid kinase activity;negative regulation of cytokine production involved in inflammatory response;positive regulation of protein localization to nucleus;positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway;positive regulation of reactive oxygen species metabolic process
• Cellular component: extracellular region;extracellular space;endoplasmic reticulum lumen;Golgi lumen;plasma membrane;external side of plasma membrane;collagen-containing extracellular matrix;extracellular exosome;blood microparticle
• Molecular function: lipopolysaccharide binding;serine-type endopeptidase activity;signaling receptor binding;calcium ion binding;protein binding;enzyme activator activity;growth factor activity;heparin binding;thrombospondin receptor activity