KNG1

kininogen 1, the group of Cystatins, type 3|Neuropeptides

Basic information

Region (hg38): 3:186717347-186744410

Previous symbols: [ "KNG", "BDK", "HK" ]

Links

ENSG00000113889 ∙ NCBI:3827 ∙ OMIM:612358 ∙ HGNC:6383 ∙ Uniprot:P01042 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital high-molecular-weight kininogen deficiency (Strong), mode of inheritance: AR
• congenital high-molecular-weight kininogen deficiency (Supportive), mode of inheritance: AR
• angioedema, hereditary, 6 (Limited), mode of inheritance: Unknown
• congenital high-molecular-weight kininogen deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Angioedema, hereditary, 6	AD	Allergy/Immunology/Infectious	Individuals with Hereditary angioedema may have episodes of angioedema, and medical management (eg, with C1INH concentrate) has been described as beneficial in at least one individual	Allergy/Immunology/Infectious; Hematologic	1202089; 1174709; 16695963; 48123; 127805; 3728458; 1968772; 7901207; 12576314; 31087670; 33114181
Most individuals with K ininogen deficiency have been reported to be asymptomatic, though one individual has been reported with cerebral artery thrombosis after moderate trauma

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KNG1 gene.

• Inborn genetic diseases (24 variants)
• High molecular weight kininogen deficiency (6 variants)
• not provided (4 variants)
• Hereditary angioedema with normal C1Inh (2 variants)
• not specified (2 variants)
• Angioedema, hereditary, 6 (1 variants)
• Thrombus (1 variants)
• Kininogen deficiency, total (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KNG1 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		2
missense			26	2		28
nonsense	3				1	4
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)	2					2
splice region				1		1
non coding						0
Total	5	0	27	4	1

Highest pathogenic variant AF is 0.0000460

Variants in KNG1

This is a list of pathogenic ClinVar variants found in the KNG1 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-186717458-T-A		Hereditary angioedema with normal C1Inh	not provided (Feb 01, 2020)
3-186717612-G-A		not specified	Uncertain significance (Mar 31, 2022)
3-186717669-A-C		not specified	Uncertain significance (May 08, 2023)
3-186717673-A-G		not specified	Uncertain significance (Dec 28, 2023)
3-186717701-G-A		KNG1-related disorder	Likely benign (Jan 20, 2020)
3-186717704-T-G		Thrombus • not specified	Uncertain significance (Dec 27, 2022)
3-186717708-T-G		Angioedema, hereditary, 6 • KNG1-related disorder	Conflicting classifications of pathogenicity (Sep 06, 2022)
3-186720155-T-C		KNG1-related disorder	Benign (Oct 21, 2019)
3-186720217-T-A		High molecular weight kininogen deficiency	Pathogenic (Sep 04, 2023)
3-186722440-A-T		not specified	Uncertain significance (Oct 10, 2023)
3-186722453-C-T		not specified	Uncertain significance (Aug 12, 2021)
3-186722454-G-A		KNG1-related disorder	Benign (Oct 17, 2019)
3-186722480-C-T			Likely benign (May 01, 2023)
3-186722504-C-A		not specified	Uncertain significance (Dec 21, 2022)
3-186722513-T-G		not specified	Uncertain significance (Dec 14, 2023)
3-186725117-G-A		Hereditary angioedema with normal C1Inh	not provided (Feb 01, 2020)
3-186725156-C-G		not specified	Uncertain significance (May 03, 2023)
3-186725184-G-A		not specified	Uncertain significance (Jan 09, 2024)
3-186727258-C-T		Kininogen deficiency, total • High molecular weight kininogen deficiency	Pathogenic (Sep 04, 2023)
3-186727259-G-A		not specified	Uncertain significance (Jul 06, 2021)
3-186727263-T-G		KNG1-related disorder	Benign (Nov 04, 2019)
3-186727318-C-G		not specified	Uncertain significance (Jan 23, 2024)
3-186731551-G-A		not specified	Uncertain significance (Feb 27, 2023)
3-186731575-A-G		not specified	Likely benign (Oct 06, 2023)
3-186731583-T-G		not specified	Uncertain significance (Jun 09, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KNG1	protein_coding	protein_coding	ENST00000265023	10	26679

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.21e-10	0.913	125692	0	55	125747	0.000219

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.112	363	357	1.02	0.0000188	4275
Missense in Polyphen		79	73.043	1.0816		920
Synonymous	-0.750	143	132	1.08	0.00000760	1198
Loss of Function	1.90	20	31.5	0.634	0.00000180	342

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000735	0.000728
Ashkenazi Jewish	0.00	0.00
East Asian	0.000494	0.000489
Finnish	0.00	0.00
European (Non-Finnish)	0.000195	0.000193
Middle Eastern	0.000494	0.000489
South Asian	0.000229	0.000229
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: (1) Kininogens are inhibitors of thiol proteases; (2) HMW-kininogen plays an important role in blood coagulation by helping to position optimally prekallikrein and factor XI next to factor XII; (3) HMW-kininogen inhibits the thrombin- and plasmin- induced aggregation of thrombocytes; (4) the active peptide bradykinin that is released from HMW-kininogen shows a variety of physiological effects: (4A) influence in smooth muscle contraction, (4B) induction of hypotension, (4C) natriuresis and diuresis, (4D) decrease in blood glucose level, (4E) it is a mediator of inflammation and causes (4E1) increase in vascular permeability, (4E2) stimulation of nociceptors (4E3) release of other mediators of inflammation (e.g. prostaglandins), (4F) it has a cardioprotective effect (directly via bradykinin action, indirectly via endothelium-derived relaxing factor action); (5) LMW-kininogen inhibits the aggregation of thrombocytes; (6) LMW- kininogen is in contrast to HMW-kininogen not involved in blood clotting.
• Disease: DISEASE: High molecular weight kininogen deficiency (HMWK deficiency) [MIM:228960]: Autosomal recessive coagulation defect. Patients with HWMK deficiency do not have a hemorrhagic tendency, but they exhibit abnormal surface-mediated activation of fibrinolysis. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Agents Acting on the Renin-Angiotensin System Pathway, Pharmacodynamics;Complement and coagulation cascades - Homo sapiens (human);ACE Inhibitor Pathway, Pharmacodynamics;Vitamin D Receptor Pathway;Dengue-2 Interactions with Complement and Coagulation Cascades;ACE Inhibitor Pathway;Complement and Coagulation Cascades;Signaling by GPCR;Signal Transduction;corticosteroids and cardioprotection;ion channels and their functional role in vascular endothelium;vegf hypoxia and angiogenesis;intrinsic prothrombin activation pathway;Post-translational protein phosphorylation;Post-translational protein modification;Metabolism of proteins;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Peptide ligand-binding receptors;Class A/1 (Rhodopsin-like receptors);actions of nitric oxide in the heart;GPCR ligand binding;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);GPCR signaling-G alpha s Epac and ERK;Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;GPCR signaling-G alpha s PKA and ERK;Intrinsic Pathway of Fibrin Clot Formation;Hemostasis;Formation of Fibrin Clot (Clotting Cascade);G alpha (i) signalling events;GPCR signaling-G alpha i;G alpha (q) signalling events;GPCR downstream signalling;Syndecan-2-mediated signaling events;Beta2 integrin cell surface interactions (Consensus)

Recessive Scores

• pRec: 0.236

Intolerance Scores

• loftool: 0.920
• rvis_EVS: 0.2
• rvis_percentile_EVS: 67.43

Haploinsufficiency Scores

• pHI: 0.348
• hipred: N
• hipred_score: 0.298
• ghis: 0.426

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.553

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Kng2
• Phenotype: growth/size/body region phenotype

Zebrafish Information Network

• Gene name: kng1
• Affected structure: pharyngeal arch 1
• Phenotype tag: abnormal
• Phenotype quality: disorganized

Gene ontology

• Biological process: platelet degranulation;inflammatory response;negative regulation of cell adhesion;G protein-coupled receptor signaling pathway;positive regulation of cytosolic calcium ion concentration;blood coagulation, intrinsic pathway;negative regulation of endopeptidase activity;negative regulation of blood coagulation;vasodilation;positive regulation of apoptotic process;post-translational protein modification;cellular protein metabolic process;negative regulation of proteolysis
• Cellular component: extracellular region;extracellular space;endoplasmic reticulum lumen;plasma membrane;platelet alpha granule lumen;collagen-containing extracellular matrix;extracellular exosome;blood microparticle
• Molecular function: cysteine-type endopeptidase inhibitor activity;signaling receptor binding;protein binding;heparin binding;zinc ion binding