GeneBe

MAP2K2

protein-coding

mitogen-activated protein kinase kinase 2, the group of Mitogen-activated protein kinase kinases

Gene summary

The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. It phosphorylates and thus activates MAPK1/ERK2 and MAPK2/ERK3. The activation of this kinase itself is dependent on the Ser/Thr phosphorylation by MAP kinase kinase kinases. Mutations in this gene cause cardiofaciocutaneous syndrome (CFC syndrome), a disease characterized by heart defects, cognitive disability, and distinctive facial features similar to those found in Noonan syndrome. The inhibition or degradation of this kinase is also found to be involved in the pathogenesis of Yersinia and anthrax. A pseudogene, which is located on chromosome 7, has been identified for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:
  • PRKMK2

MANE transcript

NM_030662.4

Inheritance

AD

ClinVar variants

P:28U:436B:267

Top phenotype

Cardiofaciocutaneous syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr19:4,090,321-4,124,122

External References & Databases

Ensembl (ENSG00000126934)NCBI Gene (5605)OMIM (601263)HGNC:6842GenCCUniProt (P36507)AlphaFoldClinVar (MAP2K2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~33.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiofaciocutaneous syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015280

Submitter: ClinGen

There is a definitive association between alteration of the MAP2K2 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 MAP2K2 in patients with CFC (Narumi et al., 2007; Nava et al., 2007; Nystrom et al., 2008; Rodriguez-Viciana, Tetsu, et al., 2006). The MAP2K2 gene is also located in the Ras/MAPK pathway, which is associated with the CFC phenotype (Aoki et al., 2016; Rauen, 2013). Of note, MAP2K2 is also classified as Limited in association with Noonan syndrome (NS). The ClinGen RASopathy Expert Panel found no evidence associating MAP2K2 with NS with multiple lentigines, NS-like disorder with loose anagen hair, or Costello syndrome. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).

cardiofaciocutaneous syndrome 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014114

Submitter: G2P

Noonan syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: ClinGen

There was only sufficient evidence in the literature for the association between MAP2K2 and Noonan syndrome (NS) to be classified as Limited. Variants in MAP2K2 have only been seen in 2 patients with NS (Takenouchi et al., 2014; van Trier et al., 2015; Rodriguez-Viciana, Tetsu, et al., 2006). The MAP2K2 gene is also located in the Ras/MAPK pathway, which is associated with the NS phenotype (Aoki et al., 2016; Rauen, 2013). Of note, MAP2K2 is also classified as Definitive in association with cardiofaciocutaneous syndrome. The ClinGen RASopathy Expert Panel found no evidence associating MAP2K2 with NS with multiple lentigines, NS-like disorder with loose anagen hair, or Costello syndrome. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 6/1/18 (SOP Version 5).

cardiofaciocutaneous syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014114

Submitter: Ambry Genetics

cardiofaciocutaneous syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014114

Submitter: Labcorp Genetics (formerly Invitae)

neurofibromatosis-Noonan syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011035

Submitter: Orphanet

cardiofaciocutaneous syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015280

Submitter: Orphanet

cardiofaciocutaneous syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014114

Submitter: PanelApp Australia

cardiofaciocutaneous syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014114

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Cardiofaciocutaneous syndrome 4AD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Oncologic

Intervention: Cardiovascular; Oncologic

Rationale: Surveillance and treatment related to manifestations such as cardiac anomalies can be beneficial; Individuals with malignancies have been reported (eg, hematologic malignancies), and awareness of increased risk may be beneficial in order to allow prompt detection and management

Refs: 16439621; 8456719; 18042262; 20301365; 20358587; 21178588; 21495173Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAP2K2 variants in ClinVar

27 Conditions Cataloged
RASopathyTotal: 730
not providedTotal: 314
Cardiovascular phenotypeTotal: 258
not specifiedTotal: 225
Cardiofaciocutaneous syndrome 4Total: 120
MAP2K2-related disorderTotal: 53
Noonan syndrome and Noonan-related syndromeTotal: 34
Noonan syndromeTotal: 15

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030662.4. 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.

EffectPLPVUSLBBSum
synonymous
7
clinvar
215
clinvar
18
clinvar
 240
missense
6
clinvar
22
clinvar
386
clinvar
27
clinvar
3
clinvar
 444
nonsense
6
clinvar
 6
start loss
1
clinvar
 1
frameshift
22
clinvar
2
clinvar
 24
splice donor/acceptor (+/-2bp)
15
clinvar
1
clinvar
 16
Total62243624621731

Highest pathogenic variant AF is 0.00001118011

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_030662.4RefSeqNP_109587.111MANE Select
ENST00000262948.10EnsemblENSP00000262948.411MANE Select
NM_001440688.1RefSeqNP_001427617.19Standard
NM_001440689.1RefSeqNP_001427618.17Standard

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
  • negative regulation of gene expression
  • peptidyl-tyrosine phosphorylation
  • signal transduction by protein phosphorylation

Molecular Function

  • protein serine/threonine kinase activity
  • MAP kinase kinase activity
  • protein serine/threonine/tyrosine kinase activity
  • protein tyrosine kinase activity
  • protein binding

Cellular Component

  • extracellular region
  • nucleus
  • cytoplasm
  • mitochondrion
  • early endosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000262948
Coding exons
11
Length
33808
Individuals with no LoFs
125727
Homozygous LoFs
0
Heterozygous LoFs
14
Defined
125741
p
0.0000557
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.871752600.6740.00001792568
Missense (PolyPhen)4981.7960.59905856
Synonymous-0.4531261201.050.00000968791
Loss of Function3.66219.40.1030.00000102222

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000210.00020rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000940.000092rare
European (Non-Finnish)0.0000380.000035rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity). {ECO:0000250}.;
Disease
DISEASE: Cardiofaciocutaneous syndrome 4 (CFC4) [MIM:615280]: 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. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:18042262, ECO:0000269|PubMed:20358587}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.512

Intolerance Scores

LoFtool
0.0513
RVIS EVS
-0.8
RVIS percentile EVS
12.33

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.999

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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