MAP2K1
protein-codingmitogen-activated protein kinase kinase 1, the group of Mitogen-activated protein kinase kinases
Gene summary
The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]
- PRKMK1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~104.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014113
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007893
Submitter: ClinGen
There was only sufficient evidence in the literature for the association between MAP2K1 and Noonan syndrome with multiple lentigines (NSML) to be classified as Limited. The only published evidence supporting the association is a de novo case (Nishi et al., 2015). The MAP2K1 gene is also located in the Ras/MAPK pathway, which is associated with the NSML phenotype (Aoki et al., 2016; Rauen, 2013). Of note, MAP2K1 is classified as Definitive in association with cardiofaciocutaneous syndrome, as Limited in association with NS, and as Disputed in association with Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating MAP2K1 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 5/29/18 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0014113
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0009026
Submitter: ClinGen
There have been two studies to date that have identified patients with features consistent with Costello syndrome (CS) and de novo or inherited variants in MAP2K1 (Gripp et al., 2007; Nava et al., 2007). However, none of the patients possessed features to definitively differentiate their diagnosis from other RASopathies as CS, and both studies concluded that the cases should not be diagnosed with CS. Variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of CS versus severe forms of cardiofaciocutaneous syndrome (CFC). Therefore, the evidence for this association is Disputed. Furthermore, the HRAS gene is believed to be the only gene associated with CS (Aoki et al., 2005; Estep, Tidyman, Teitell, Cotter, & Rauen, 2006; Gripp et al., 2006; Kerr et al., 2006; Zampino et al., 2007). Of note, MAP2K1 is classified as Definitive in association with CFC and as Limited in association with Noonan syndrome (NS) and NS with multiple lentigines. The ClinGen RASopathy Expert Panel found no evidence associating MAP2K1 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0014113
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0015280
Submitter: ClinGen
There is a definitive association between alteration of the MAP2K1 gene and cardiofaciocutaneous syndrome (CFC). The maximum amount of scorable genetic evidence has been published showing de novo as well as non-de novo variants occur in MAP2K1 in patients with CFC (Cizmarova et al., 2016; Dentici et al., 2009; Gripp et al., 2007; Rodriguez-Viciana, Tetsu, et al., 2006). The MAP2K1 gene is also located in the Ras/MAPK pathway, which is associated with the CFC phenotype (Aoki et al., 2016; Rauen, 2013). Of note, MAP2K1 is classified as Limited in association with Noonan syndrome (NS) and NS with multiple lentigines and as Disputed in association with Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating MAP2K1 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 5/29/18 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0018997
Submitter: ClinGen
There was only sufficient evidence in the literature for the association between MAP2K1 and Noonan syndrome (NS) to be classified as Limited (Chen et al., 2014; Croonen et al., 2013; Nava et al., 2007; Pierpont, Semrud-Clikeman, & Pierpont, 2017). Variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of NS versus other MAP2K1-RASopathies. The MAP2K1 gene is also located in the Ras/MAPK pathway, which is associated with the NS phenotype (Aoki et al., 2016; Rauen, 2013). However, additional phenotype-genotype correlations are necessary to solidify the association of MAP2K1 with NS. Of note, MAP2K1 is classified as Definitive in association with cardiofaciocutaneous syndrome, as Limited in association with NS with multiple lentigines, and as Disputed in association with Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating MAP2K1 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0007893
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014113
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0015280
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014113
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Hematologic; Musculoskeletal; Neurologic; Oncologic
Intervention: Cardiovascular; Oncologic
Rationale: Surveillance and treatment related to manifestations such as cardiac anomalies can be beneficial; Individuals may be at increased malignancy risk (eg, an individual with hepatoplastoma has been described), and awareness may allow prompt recognition and treatment of oncologic sequelae
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MAP2K1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002755.4. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 7 | 149 | 6 | 162 | ||
| missense | 22 | 29 | 233 | 9 | 1 | 294 |
| nonsense | 3 | 3 | ||||
| start loss | 0 | |||||
| frameshift | 11 | 1 | 12 | |||
| splice donor/acceptor (+/-2bp) | 17 | 17 | ||||
| Total | 22 | 29 | 271 | 159 | 7 | 488 |
Highest pathogenic variant AF is 0.0000041043827
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002746.1 | 11 | MANE Select | |
| Ensembl | ENSP00000302486.5 | 11 | MANE Select | |
| RefSeq | NP_001397994.1 | 10 | Standard | |
| Ensembl | ENSP00000456438.1 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Prion diseases - Homo sapiens (human)
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Non-small cell lung cancer - Homo sapiens (human)
- Chronic myeloid leukemia - Homo sapiens (human)
- Gastric cancer - Homo sapiens (human)
Biological Process
- MAPK cascade
- activation of MAPK activity
- protein phosphorylation
- chemotaxis
- cell cycle arrest
Molecular Function
- protein kinase activity
- protein serine/threonine kinase activity
- MAP kinase kinase activity
- protein serine/threonine/tyrosine kinase activity
- protein tyrosine kinase activity
Cellular Component
- nucleus
- cytoplasm
- mitochondrion
- early endosome
- late endosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000307102
- Coding exons
- 11
- Length
- 105496
- Individuals with no LoFs
- 125737
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 10
- Defined
- 125747
- p
- 0.0000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.11 | 88 | 217 | 0.406 | 0.0000121 | 2593 |
| Missense (PolyPhen) | 13 | 71.987 | 0.18059 | 926 | ||
| Synonymous | -0.650 | 93 | 85.4 | 1.09 | 0.00000559 | 753 |
| Loss of Function | 3.59 | 3 | 20.6 | 0.146 | 0.00000106 | 251 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator- activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis. {ECO:0000269|PubMed:14737111, ECO:0000269|PubMed:17101779}.;
- Disease
- DISEASE: Cardiofaciocutaneous syndrome 3 (CFC3) [MIM:615279]: A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. Distinctive features of CFC3 include macrostomia and horizontal shape of palpebral fissures. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:18042262}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.849
Intolerance Scores
- LoFtool
- 0.0532
- RVIS EVS
- -0.45
- RVIS percentile EVS
- 24
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.997
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Medium |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Medium | Medium |