NF2

protein-coding

NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor, the group of A-kinase anchoring proteins|FERM domain containing

Gene summary

This gene encodes a protein that is similar to some members of the ERM (ezrin, radixin, moesin) family of proteins that link cytoskeletal components with proteins in the cell membrane. The encoded protein is involved in regulation of contact-dependent inhibition of cell proliferation and functions in cell-cell adhesion and transmembrane signaling. The encoded protein has been shown to interact with cell-surface proteins, proteins involved in cytoskeletal dynamics, and proteins involved in regulating ion transport. Disruption of this protein's function has been implicated in tumorigenesis and metastasis. Mutations in this gene are associated with neurofibromatosis type II which is characterized by nervous system and skin tumors and ocular abnormalities. [provided by RefSeq, May 2022]

MANE transcript

NM_000268.4

Inheritance

ClinVar variants

P:298U:1125B:567

Top phenotype

Schwannomatosis, vestibular (Neurofibromatosis type II)

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr22:29,603,553-29,698,598

External References & Databases

Ensembl (ENSG00000186575)

Transcript & Mutation Effects

hg38 • Region Span ~95.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

NF2-related schwannomatosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007039

Submitter: G2P

NF2-related schwannomatosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007039

Submitter: Orphanet

NF2-related schwannomatosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007039

Submitter: ClinGen

The first report indicating a relationship of the NF2 gene with autosomal dominant Neurofibromatosis type 2 was reported by Rouleau et al., 1993 (PMID: 8379998), albeit neurofibromatosis (subtypes not defined) was a widely recognized pathologic clinical entity in the late 19th century (Ahn et al., 1994; PMID: 25996397). Neurofibromatosis type 2 is characterized by the formation of benign bilateral or unilateral tumors (schwannomas, meningiomas, gliomas, and/or neurofibromas) in the central nervous, most commonly on the eighth cranial nerve (reviewed on www.ctf.org). Current evidence suggests a prevalence of Neurofibromatosis type 2 of 1 in 25,000 (www.ctf.org). Numerous variants have been reported, in both ClinVar and in LOVD (https://databases.lovd.nl/shared/genes/NF2). Evidence supporting this gene-disease relationship includes case-level data, segregation data, functional data, and model organisms. This gene-disease relationship has been studied for more than 20 years, therefore a significant amount of case-level data, segregation data, and experimental data is available and the maximum score for genetic evidence (12 points) and experimental evidence (6 points) has been reached. Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship. In particular, earlier compelling evidence suggestive of the gene-disease relationship, such as linkage data, may not be reflected in the current curation. The mechanism for the gene-disease relationship is protein loss of function, as the NF2 protein product, termed Merlin or Schwannomin, is a tumor suppressor protein (Trofatter et al., 1993; PMID: 8453669). NF2 tumor suppressor function is regulated by the protein confirmation, with the closed form acting as the active tumor suppressor form (reviewed in Cooper and Giancotti, 2014 PMID:24726726). NF2 has been associated with multiple disease entities and/or phenotypes, including: (1) Meningioma, NF2-related, somatic (MIM: 607174) (2) Schwannomatosis, somatic Of note, these other phenotypes are noted as somatic, and therefore are not represented/ counted in this gene-disease relationship, and will be assessed separately. In summary, NF2 is DEFINITIVELY associated with autosomal dominant Neurofibromatosis Type 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Expert Panel on February 27, 2019.

NF2-related schwannomatosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007039

Submitter: Labcorp Genetics (formerly Invitae)

familial meningiomaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011789

Submitter: Ambry Genetics

NF2-related schwannomatosisDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007039

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Schwannomatosis, vestibular (Neurofibromatosis type II)AD

Manifestation: Oncologic

Intervention: Oncologic

Rationale: In order to detect neoplasms (individuals are predisposed to a variety of types of central nervous system tumors), surveillance with regular cranial MRI is indicated, which may allow detection and treatment; In the treatment of neoplasms, radiation therapy should be avoided (especially in childhood) due to the risk of causing or accelerating other neoplasms

Refs: 5304294; 4990044; 1479599; 1479598; 8379998; 7913580; 7747758; 8188242; 8751853; 8755919; 9399891; 9643284; 9811917; 9817927; 9863591; 10569966; 10220142; 9874852; 10771486; 11159946; 11342693; 11425952; 12136076; 12235555; 12473765; 12011146; 12566519; 15190457; 15235024; 15831594; 15994874; 16341811; 16521120; 16534111; 16983642; 19476995; 19880713; 20301380; 21451418; 21358190; 22038540; 22098617; 22929112; 22931905; 22989157; 23682341; 23921933; 23931824; 23939548

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NF2 variants in ClinVar

21 Conditions Cataloged

Neurofibromatosis, type 2Total: 1760

Hereditary cancer-predisposing syndromeTotal: 1405

not providedTotal: 263

not specifiedTotal: 111

Familial meningiomaTotal: 94

NF2-related disorderTotal: 58

SMARCB1-related schwannomatosisTotal: 17

MeningiomaTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000268.4. 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		3 clinvar	13 clinvar	487 clinvar	1 clinvar	504
missense	4 clinvar	11 clinvar	1061 clinvar	77 clinvar	1 clinvar	1154
nonsense	79 clinvar	6 clinvar	9 clinvar			94
start loss	2 clinvar	1 clinvar	4 clinvar			7
frameshift	102 clinvar	16 clinvar	23 clinvar			141
splice donor/acceptor (+/-2bp)	47 clinvar	27 clinvar	15 clinvar	1 clinvar		90
Total	234	64	1125	565	2	1990

Highest pathogenic variant AF is 0.0000013683522

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 70 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000268.4	RefSeq	NP_000259.1	16	MANE Select
ENST00000338641.10	Ensembl	ENSP00000344666.5	16	MANE Select
NM_001407053.1	RefSeq	NP_001393982.1	15	Standard
NM_001407054.1	RefSeq	NP_001393983.1	15	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nf2b	Danio rerio	Structure: hepatocyte Quality: increased distance abnormal

Gene / Model

Organism

Observed Phenotype

nf2b

Danio rerio

Structure: hepatocyte

Quality: increased distance

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tight junction - Homo sapiens (human)
Hippo signaling pathway - Homo sapiens (human)
Hippo signaling pathway - multiple species - Homo sapiens (human)
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase

Biological Process

mesoderm formation
negative regulation of cell-matrix adhesion
negative regulation of protein kinase activity
ectoderm development
negative regulation of cell population proliferation

Molecular Function

actin binding
protein binding

Cellular Component

nucleus
nucleolus
cytoplasm
early endosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000338641
Coding exons: 16
Length: 95043
Individuals with no LoFs: 125744
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125747
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.29	208	324	0.642	0.0000193	3952
Missense (PolyPhen)		48	109.29	0.43919		1418
Synonymous	0.126	123	125	0.986	0.00000799	1057
Loss of Function	5.44	0	34.5	0.00	0.00000176	416

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, a signaling pathway that plays a pivotal role in tumor suppression by restricting proliferation and promoting apoptosis. Along with WWC1 can synergistically induce the phosphorylation of LATS1 and LATS2 and can probably function in the regulation of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway. May act as a membrane stabilizing protein. May inhibit PI3 kinase by binding to AGAP2 and impairing its stimulating activity. Suppresses cell proliferation and tumorigenesis by inhibiting the CUL4A-RBX1-DDB1-VprBP/DCAF1 E3 ubiquitin-protein ligase complex. {ECO:0000269|PubMed:20159598, ECO:0000269|PubMed:20178741, ECO:0000269|PubMed:21167305}.;
Disease: DISEASE: Neurofibromatosis 2 (NF2) [MIM:101000]: Genetic disorder characterized by bilateral vestibular schwannomas (formerly called acoustic neuromas), schwannomas of other cranial and peripheral nerves, meningiomas, and ependymomas. It is inherited in an autosomal dominant fashion with full penetrance. Affected individuals generally develop symptoms of eighth-nerve dysfunction in early adulthood, including deafness and balance disorder. Although the tumors of NF2 are histologically benign, their anatomic location makes management difficult, and patients suffer great morbidity and mortality. {ECO:0000269|PubMed:10090912, ECO:0000269|PubMed:10669747, ECO:0000269|PubMed:10790209, ECO:0000269|PubMed:12709270, ECO:0000269|PubMed:20178741, ECO:0000269|PubMed:20445339, ECO:0000269|PubMed:7666400, ECO:0000269|PubMed:7759081, ECO:0000269|PubMed:7913580, ECO:0000269|PubMed:8081368, ECO:0000269|PubMed:8230593, ECO:0000269|PubMed:8566958, ECO:0000269|PubMed:8698340, ECO:0000269|PubMed:9643284}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Schwannomatosis 1 (SWNTS1) [MIM:162091]: A cancer syndrome in which patients develop multiple non-vestibular schwannomas, benign neoplasms that arise from Schwann cells of the cranial, peripheral, and autonomic nerves. {ECO:0000269|PubMed:18072270}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mesothelioma, malignant (MESOM) [MIM:156240]: An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle- shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos. {ECO:0000269|PubMed:12136076}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.357

Intolerance Scores

LoFtool: 0.00841
RVIS EVS: -0.87
RVIS percentile EVS: 10.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.688

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium