RAPGEF2
Rap guanine nucleotide exchange factor 2, the group of MicroRNA protein coding host genes|PDZ domain containing
Basic information
Region (hg38): 4:159103013-159360174
Previous symbols: [ "PDZGEF1" ]
Links
Phenotypes
GenCC
Source:
- amyotrophic lateral sclerosis (Limited), mode of inheritance: AD
- epilepsy, familial adult myoclonic, 7 (Limited), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Epilepsy, familial adult myoclonic, 7 | AD | General | Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing | Neurologic | 29507423 |
ClinVar
This is a list of variants' phenotypes submitted to
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the RAPGEF2 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 | 16 | |||||
| missense | 71 | 72 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| inframe indel | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| splice region | 1 | 1 | 2 | |||
| non coding | 5 | |||||
| Total | 0 | 0 | 72 | 9 | 12 |
Variants in RAPGEF2
This is a list of pathogenic ClinVar variants found in the RAPGEF2 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 4-159104215-C-T | Epilepsy, familial adult myoclonic, 7 | Uncertain significance (Mar 26, 2024) | ||
| 4-159238797-C-A | Epilepsy, familial adult myoclonic, 7 | Benign (Nov 07, 2021) | ||
| 4-159268159-A-G | not specified | Uncertain significance (Jan 23, 2023) | ||
| 4-159268171-A-C | not specified | Uncertain significance (Oct 25, 2022) | ||
| 4-159268192-A-C | not specified | Uncertain significance (Aug 28, 2024) | ||
| 4-159268210-C-A | not specified | Uncertain significance (Jul 20, 2022) | ||
| 4-159304389-A-C | Benign (Dec 31, 2019) | |||
| 4-159304409-C-A | not specified | Uncertain significance (Dec 06, 2021) | ||
| 4-159304469-A-G | not specified | Uncertain significance (Aug 16, 2021) | ||
| 4-159314734-G-C | Epilepsy, familial adult myoclonic, 7 | Uncertain significance (May 14, 2020) | ||
| 4-159322337-T-C | Benign (Dec 31, 2019) | |||
| 4-159322350-A-G | not specified | Uncertain significance (Aug 28, 2024) | ||
| 4-159322373-T-C | Likely benign (Oct 01, 2022) | |||
| 4-159323504-T-G | not specified | Uncertain significance (May 07, 2024) | ||
| 4-159323581-G-A | not specified | Uncertain significance (Jun 13, 2023) | ||
| 4-159330265-A-ATG | Epilepsy, familial adult myoclonic, 7 | Benign (Nov 07, 2021) | ||
| 4-159330265-A-ATGTG | Epilepsy, familial adult myoclonic, 7 | Benign (Nov 07, 2021) | ||
| 4-159330425-C-G | not specified | Uncertain significance (Dec 16, 2023) | ||
| 4-159330436-A-G | not specified | Uncertain significance (Mar 01, 2024) | ||
| 4-159330463-T-C | Likely benign (Mar 30, 2018) | |||
| 4-159330478-G-C | not specified | Uncertain significance (Jan 29, 2024) | ||
| 4-159331475-C-T | Benign (Dec 28, 2017) | |||
| 4-159331500-C-G | not specified | Uncertain significance (Apr 07, 2022) | ||
| 4-159331662-C-T | Benign (Mar 30, 2018) | |||
| 4-159331711-T-A | not specified | Uncertain significance (Feb 01, 2023) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| RAPGEF2 | protein_coding | protein_coding | ENST00000264431 | 24 | 255992 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.00 | 0.00000127 | 124782 | 0 | 12 | 124794 | 0.0000481 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 3.62 | 532 | 824 | 0.645 | 0.0000442 | 9877 |
| Missense in Polyphen | 103 | 268.7 | 0.38332 | 3432 | ||
| Synonymous | -0.378 | 307 | 299 | 1.03 | 0.0000171 | 2871 |
| Loss of Function | 7.06 | 8 | 73.1 | 0.109 | 0.00000427 | 834 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00 | 0.00 |
| Ashkenazi Jewish | 0.0000993 | 0.0000993 |
| East Asian | 0.000111 | 0.000111 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000626 | 0.0000618 |
| Middle Eastern | 0.000111 | 0.000111 |
| South Asian | 0.0000367 | 0.0000327 |
| Other | 0.000165 | 0.000165 |
dbNSFP
Source:
- Function
- FUNCTION: Functions as a guanine nucleotide exchange factor (GEF), which activates Rap and Ras family of small GTPases by exchanging bound GDP for free GTP in a cAMP-dependent manner. Serves as a link between cell surface receptors and Rap/Ras GTPases in intracellular signaling cascades. Acts also as an effector for Rap1 by direct association with Rap1-GTP thereby leading to the amplification of Rap1-mediated signaling. Shows weak activity on HRAS. It is controversial whether RAPGEF2 binds cAMP and cGMP (PubMed:23800469, PubMed:10801446) or not (PubMed:10608844, PubMed:10548487, PubMed:11359771). Its binding to ligand-activated beta-1 adrenergic receptor ADRB1 leads to the Ras activation through the G(s)-alpha signaling pathway. Involved in the cAMP- induced Ras and Erk1/2 signaling pathway that leads to sustained inhibition of long term melanogenesis by reducing dendrite extension and melanin synthesis. Provides also inhibitory signals for cell proliferation of melanoma cells and promotes their apoptosis in a cAMP-independent nanner. Regulates cAMP-induced neuritogenesis by mediating the Rap1/B-Raf/ERK signaling through a pathway that is independent on both PKA and RAPGEF3/RAPGEF4. Involved in neuron migration and in the formation of the major forebrain fiber connections forming the corpus callosum, the anterior commissure and the hippocampal commissure during brain development. Involved in neuronal growth factor (NGF)-induced sustained activation of Rap1 at late endosomes and in brain- derived neurotrophic factor (BDNF)-induced axon outgrowth of hippocampal neurons. Plays a role in the regulation of embryonic blood vessel formation and in the establishment of basal junction integrity and endothelial barrier function. May be involved in the regulation of the vascular endothelial growth factor receptor KDR and cadherin CDH5 expression at allantois endothelial cell-cell junctions. {ECO:0000269|PubMed:10548487, ECO:0000269|PubMed:10608844, ECO:0000269|PubMed:10608883, ECO:0000269|PubMed:10801446, ECO:0000269|PubMed:10934204, ECO:0000269|PubMed:11359771, ECO:0000269|PubMed:12391161, ECO:0000269|PubMed:16272156, ECO:0000269|PubMed:17724123, ECO:0000269|PubMed:21840392, ECO:0000269|PubMed:23800469}.;
- Pathway
- Tight junction - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Intracellular Signalling Through Adenosine Receptor A2b and Adenosine;Intracellular Signalling Through Adenosine Receptor A2a and Adenosine;MAPK Signaling Pathway;Signal Transduction;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades
(Consensus)
Recessive Scores
- pRec
- 0.133
Intolerance Scores
- loftool
- 0.255
- rvis_EVS
- -1.66
- rvis_percentile_EVS
- 2.72
Haploinsufficiency Scores
- pHI
- 0.577
- hipred
- Y
- hipred_score
- 0.822
- ghis
- 0.649
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.828
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Rapgef2
- Phenotype
- liver/biliary system phenotype; embryo 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); 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; 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; cellular 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;
Zebrafish Information Network
- Gene name
- rapgef2
- Affected structure
- pronephric glomerulus
- Phenotype tag
- abnormal
- Phenotype quality
- permeability
Gene ontology
- Biological process
- MAPK cascade;blood vessel development;neuron migration;G protein-coupled receptor signaling pathway;neuropeptide signaling pathway;small GTPase mediated signal transduction;negative regulation of cell population proliferation;positive regulation of neuron projection development;cAMP-mediated signaling;ventricular system development;forebrain neuron development;microvillus assembly;neuron projection development;brain-derived neurotrophic factor receptor signaling pathway;positive regulation of protein binding;Rap protein signal transduction;intracellular signal transduction;nerve growth factor signaling pathway;positive regulation of GTPase activity;positive regulation of cAMP-mediated signaling;positive regulation of protein kinase activity;negative regulation of melanin biosynthetic process;regulation of synaptic plasticity;negative regulation of dendrite morphogenesis;establishment of endothelial barrier;positive regulation of ERK1 and ERK2 cascade;cellular response to cAMP;cellular response to cGMP;adenylate cyclase-activating adrenergic receptor signaling pathway;protein localization to plasma membrane;establishment of endothelial intestinal barrier;regulation of cell junction assembly;cellular response to nerve growth factor stimulus;positive regulation of cAMP-dependent protein kinase activity;positive regulation of dendritic cell apoptotic process;positive regulation of vasculogenesis;positive regulation of neuron migration
- Cellular component
- cytoplasm;late endosome;cytosol;plasma membrane;integral component of plasma membrane;cell-cell junction;bicellular tight junction;membrane;apical plasma membrane;endocytic vesicle;protein-containing complex;neuron projection;neuronal cell body;synapse;perinuclear region of cytoplasm
- Molecular function
- Ras guanyl-nucleotide exchange factor activity;GTPase activator activity;calcium ion binding;protein binding;Rap guanyl-nucleotide exchange factor activity;diacylglycerol binding;PDZ domain binding;cAMP binding;cGMP binding;beta-1 adrenergic receptor binding;WW domain binding;phosphatidic acid binding