GeneBe

KNG1

protein-coding

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

Gene summary

This gene uses alternative splicing to generate two different proteins- high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK). HMWK is essential for blood coagulation and assembly of the kallikrein-kinin system. Also, bradykinin, a peptide causing numerous physiological effects, is released from HMWK. Bradykinin also functions as an antimicrobial peptide with antibacterial and antifungal activity. In contrast to HMWK, LMWK is not involved in blood coagulation. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduces or depletes angiotensin converting enzyme 2 (ACE2), which results in an increase in levels of des-Arg(9)-bradykinin, a bioactive metabolite of bradykinin that is associated with lung injury and inflammation. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2020]

Previous symbols:
  • KNG
  • BDK
  • HK

MANE transcript

NM_001102416.3

Inheritance

AD, AR

ClinVar variants

P:10U:106B:22

Top phenotype

Angioedema, hereditary, 6

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr3:186,717,348-186,744,410

External References & Databases

Ensembl (ENSG00000113889)NCBI Gene (3827)OMIM (612358)HGNC:6383GenCCUniProt (P01042)AlphaFoldClinVar (KNG1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~27.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

angioedema, hereditary, 6LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0023660

Submitter: Labcorp Genetics (formerly Invitae)

angioedema, hereditary, 6MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0023660

Submitter: PanelApp Australia

congenital high-molecular-weight kininogen deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009234

Submitter: ClinGen

KNG1 was first reported in relation to high molecular weight kininogen (HMWK) deficiency in 1990 (Hayashi et al, PMID: 1968772). This curation is considered a gene-deficiency curation, due to the lack of evidence supporting this gene being involved in any disease or disorder beyond a prolonged PTT. Evidence supporting this gene-deficiency curation includes case-level data, segregation data, and experimental data. At least 6 unique variants (nonsense and frameshift) have been reported in humans. Variants in this gene have been reported in at least 8 probands in over 8 publications. Variants in this gene segregated with kininogen deficiency in 2 additional family members. The gene-deficiency relationship is supported by an animal model (Merkulov et al, PMID: 18000168) and expression studies (Krijanovski et al, PMID: 12576314). In summary, KNG1 is definitively associated with (high molecular weight) kininogen deficiency. This has been repeatedly demonstrated in both the research and the clinical diagnostic settings and has been upheld over time.

congenital high-molecular-weight kininogen deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009234

Submitter: Labcorp Genetics (formerly Invitae)

congenital high-molecular-weight kininogen deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009234

Submitter: Orphanet

Clinical Genomic Database (CGD)

Angioedema, hereditary, 6AD

Manifestation: Allergy/Immunology/Infectious; Hematologic

Intervention: Allergy/Immunology/Infectious

Rationale: 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

Comments: 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

Refs: 1202089; 1174709; 16695963; 48123; 127805; 3728458; 1968772; 7901207; 12576314; 31087670; 33114181Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KNG1 variants in ClinVar

8 Conditions Cataloged
not specifiedTotal: 107
not providedTotal: 16
High molecular weight kininogen deficiencyTotal: 9
KNG1-related disorderTotal: 5
Angioedema, hereditary, 6Total: 4
Hereditary angioedema with normal C1InhTotal: 1
ThrombusTotal: 1
KININOGEN DEFICIENCY, TOTALTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001102416.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
12
clinvar
 13
missense
2
clinvar
99
clinvar
10
clinvar
 111
nonsense
3
clinvar
1
clinvar
1
clinvar
 5
start loss
0
frameshift
2
clinvar
3
clinvar
 5
splice donor/acceptor (+/-2bp)
2
clinvar
2
clinvar
 4
Total73106220138

Highest pathogenic variant AF is 0.00001240004

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001102416.3RefSeqNP_001095886.110MANE Select
ENST00000644859.2EnsemblENSP00000493985.110MANE Select
NM_000893.4RefSeqNP_000884.111Standard
NM_001166451.2RefSeqNP_001159923.110Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
kng1Danio rerio

Structure: pharyngeal arch 1

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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

Biological Process

  • platelet degranulation
  • inflammatory response
  • negative regulation of cell adhesion
  • G protein-coupled receptor signaling pathway
  • positive regulation of cytosolic calcium ion concentration

Molecular Function

  • cysteine-type endopeptidase inhibitor activity
  • signaling receptor binding
  • protein binding
  • heparin binding
  • zinc ion binding

Cellular Component

  • extracellular region
  • extracellular space
  • endoplasmic reticulum lumen
  • plasma membrane
  • platelet alpha granule lumen

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000265023
Coding exons
10
Length
26679
Individuals with no LoFs
125692
Homozygous LoFs
0
Heterozygous LoFs
55
Defined
125747
p
0.000219
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.1123633571.020.00001884275
Missense (PolyPhen)7973.0431.0816920
Synonymous-0.7501431321.080.000007601198
Loss of Function1.902031.50.6340.00000180342

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000560.00055rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish00.0absent
East Asian0.000490.00049rare
Finnish00.0absent
European (Non-Finnish)0.000190.00019rare
South Asian0.000230.00023rare
Other0.000330.00033rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.236

Intolerance Scores

LoFtool
0.920
RVIS EVS
0.2
RVIS percentile EVS
67.43

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.553

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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