KRIT1
KRIT1 ankyrin repeat containing, the group of CCM adhesion complex|FERM domain containing|Ankyrin repeat domain containing|MicroRNA protein coding host genes
Basic information
Region (hg38): 7:92197497-92246166
Previous symbols: [ "CCM1" ]
Links
Phenotypes
GenCC
Source:
- cerebral cavernous malformation 1 (Strong), mode of inheritance: AD
- cerebral cavernous malformation 1 (Definitive), mode of inheritance: AD
- famililal cerebral cavernous malformations (Supportive), mode of inheritance: AD
- cerebral cavernous malformation 1 (Definitive), mode of inheritance: AD
- cerebral cavernous malformation 1 (Strong), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Cerebral cavernous malformations 1 | AD | Cardiovascular; Neurologic; Pharmacogenomic | Surveillance measures (eg, spinal cord MRI, annual brain gradient echo or susceptibility-weighted imaging) has been advocated; Agents that increase risk of hemorrhage should be avoided (eg, aspirin, NSAIDs, heparin, warfarin) | Cardiovascular; Dermatologic; Neurologic | 10508515; 10545614; 10814716; 11222804; 11310633; 11161805; 12404106; 11831930; 11914398; 15079030; 17562932; 17211633; 18060436; 18207546; 19099113; 19453802; 19454328; 20301470; 20306072; 20646827; 20689144; 20884211; 21029238; 22261708; 22510019; 22699465; 23584803; 23663874; 23806994; 23828392; 24007869; 24058906 |
ClinVar
This is a list of variants' phenotypes submitted to
- Cerebral cavernous malformation (382 variants)
- not provided (191 variants)
- Angiokeratoma corporis diffusum with arteriovenous fistulas (79 variants)
- Inborn genetic diseases (54 variants)
- not specified (25 variants)
- KRIT1-related condition (13 variants)
- Cerebral cavernous malformation 1 (8 variants)
- KRIT1-Related Disorders (2 variants)
- See cases (2 variants)
- Seizure (2 variants)
- Cavernous hemangioma (2 variants)
- Hereditary cavernous hemangioma of brain (1 variants)
- Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the KRIT1 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 | 47 | 52 | ||||
| missense | 95 | 107 | ||||
| nonsense | 67 | 17 | 85 | |||
| start loss | 1 | |||||
| frameshift | 104 | 28 | 133 | |||
| inframe indel | 1 | |||||
| splice donor/acceptor (+/-2bp) | 23 | 14 | 38 | |||
| splice region ? | 2 | 5 | 13 | 6 | 1 | 27 |
| non coding ? | 37 | 21 | 17 | 77 | ||
| Total | 197 | 63 | 140 | 76 | 18 |
Highest pathogenic variant AF is 0.0000131
Variants in KRIT1
This is a list of pathogenic ClinVar variants found in the KRIT1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 7-92198986-G-A | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Benign/Likely benign (Jan 12, 2018) | ||
| 7-92199034-T-C | Cerebral cavernous malformation • Angiokeratoma corporis diffusum with arteriovenous fistulas | Benign (Jan 13, 2018) | ||
| 7-92199081-A-C | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Uncertain significance (Jan 13, 2018) | ||
| 7-92199181-T-C | Cerebral cavernous malformation • Angiokeratoma corporis diffusum with arteriovenous fistulas | Uncertain significance (Jan 13, 2018) | ||
| 7-92199206-A-G | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Benign/Likely benign (Jan 13, 2018) | ||
| 7-92199279-A-G | Cerebral cavernous malformation • Angiokeratoma corporis diffusum with arteriovenous fistulas | Uncertain significance (Jan 13, 2018) | ||
| 7-92199292-A-C | Cerebral cavernous malformation • Angiokeratoma corporis diffusum with arteriovenous fistulas | Benign (Jan 12, 2018) | ||
| 7-92199351-T-C | Cerebral cavernous malformation • Angiokeratoma corporis diffusum with arteriovenous fistulas | Benign (Jan 12, 2018) | ||
| 7-92199373-A-C | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Benign/Likely benign (Jun 01, 2023) | ||
| 7-92199379-T-G | Cerebral cavernous malformation • Angiokeratoma corporis diffusum with arteriovenous fistulas | Uncertain significance (Feb 09, 2018) | ||
| 7-92199401-A-G | Cerebral cavernous malformation • Angiokeratoma corporis diffusum with arteriovenous fistulas | Benign (Jan 12, 2018) | ||
| 7-92199531-A-G | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Uncertain significance (Jan 12, 2018) | ||
| 7-92199707-A-C | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Uncertain significance (Mar 30, 2018) | ||
| 7-92199818-G-A | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Uncertain significance (Jan 13, 2018) | ||
| 7-92199851-T-A | Cerebral cavernous malformation • Angiokeratoma corporis diffusum with arteriovenous fistulas | Uncertain significance (Jan 12, 2018) | ||
| 7-92199877-G-A | Cerebral cavernous malformation • Angiokeratoma corporis diffusum with arteriovenous fistulas | Uncertain significance (Jan 13, 2018) | ||
| 7-92200088-T-C | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Uncertain significance (Jan 12, 2018) | ||
| 7-92200158-T-C | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Uncertain significance (Jan 13, 2018) | ||
| 7-92200285-A-G | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Uncertain significance (Jan 13, 2018) | ||
| 7-92200286-T-A | Cerebral cavernous malformation • Angiokeratoma corporis diffusum with arteriovenous fistulas | Uncertain significance (Jan 12, 2018) | ||
| 7-92200300-G-A | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Uncertain significance (Jan 13, 2018) | ||
| 7-92200357-A-AT | Cerebral cavernous malformation • Angiokeratoma corporis diffusum with arteriovenous fistulas | Benign (Jun 14, 2016) | ||
| 7-92200364-T-TC | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Uncertain significance (Jun 14, 2016) | ||
| 7-92200375-G-C | Cerebral cavernous malformation • Angiokeratoma corporis diffusum with arteriovenous fistulas | Uncertain significance (Jan 12, 2018) | ||
| 7-92200405-C-T | Angiokeratoma corporis diffusum with arteriovenous fistulas • Cerebral cavernous malformation | Uncertain significance (Jan 12, 2018) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| KRIT1 | protein_coding | protein_coding | ENST00000394507 | 16 | 47198 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.000693 | 0.999 | 125720 | 0 | 24 | 125744 | 0.0000954 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.43 | 315 | 395 | 0.798 | 0.0000198 | 4858 |
| Missense in Polyphen | 96 | 135.84 | 0.70673 | 1706 | ||
| Synonymous | -0.244 | 129 | 126 | 1.03 | 0.00000580 | 1332 |
| Loss of Function | 4.18 | 14 | 43.8 | 0.319 | 0.00000237 | 527 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000174 | 0.000174 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.000109 | 0.000109 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000969 | 0.0000967 |
| Middle Eastern | 0.000109 | 0.000109 |
| South Asian | 0.000163 | 0.000163 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity (By similarity). Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits ERK1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establish and maintain correct endothelial cell polarity and vascular lumen and these effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction, and cell junction stabilization. Plays a role in integrin signaling via its interaction with ITGB1BP1; this prevents the interaction between ITGB1 and ITGB1BP1. Microtubule- associated protein that binds to phosphatidylinositol 4,5- bisphosphate (PIP2)-containing membranes in a GTP-bound RAP1- dependent manner. Plays an important role in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage. Regulates the homeostasis of intracellular ROS through an antioxidant pathway involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1 (CCND1) levels required for cell transition from proliferative growth to quiescence by preventing the accumulation of intracellular ROS through the modulation of FOXO1 and SOD2 levels. {ECO:0000250|UniProtKB:Q6S5J6, ECO:0000269|PubMed:11741838, ECO:0000269|PubMed:17916086, ECO:0000269|PubMed:20332120, ECO:0000269|PubMed:20616044, ECO:0000269|PubMed:20668652, ECO:0000269|PubMed:21633110, ECO:0000269|PubMed:23317506}.;
- Disease
- DISEASE: Cerebral cavernous malformations 1 (CCM1) [MIM:116860]: A congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. {ECO:0000269|PubMed:12172908}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Rap1 signaling pathway - Homo sapiens (human)
(Consensus)
Recessive Scores
- pRec
- 0.416
Intolerance Scores
- loftool
- 0.845
- rvis_EVS
- -0.87
- rvis_percentile_EVS
- 10.8
Haploinsufficiency Scores
- pHI
- 0.160
- hipred
- Y
- hipred_score
- 0.793
- ghis
- 0.663
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.926
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Krit1
- Phenotype
- vision/eye phenotype; limbs/digits/tail 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); neoplasm; 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); 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); embryo phenotype; craniofacial phenotype; muscle phenotype; growth/size/body region 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);
Zebrafish Information Network
- Gene name
- krit1
- Affected structure
- endothelial cell
- Phenotype tag
- abnormal
- Phenotype quality
- increased distribution
Gene ontology
- Biological process
- angiogenesis;negative regulation of endothelial cell proliferation;small GTPase mediated signal transduction;negative regulation of endothelial cell migration;negative regulation of angiogenesis;cell redox homeostasis;regulation of catalytic activity;regulation of establishment of cell polarity;negative regulation of endothelial cell apoptotic process
- Cellular component
- extracellular space;cytoplasm;microtubule;plasma membrane;cell-cell junction
- Molecular function
- protein binding;phosphatidylinositol-4,5-bisphosphate binding;microtubule binding;GTPase regulator activity;protein-containing complex binding