NF2

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

Basic information

Region (hg38): 22:29603555-29698598

Links

ENSG00000186575 ∙ NCBI:4771 ∙ OMIM:607379 ∙ HGNC:7773 ∙ Uniprot:P35240 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurofibromatosis type 2 (Strong), mode of inheritance: AD
• familial meningioma (Limited), mode of inheritance: Unknown
• neurofibromatosis type 2 (Definitive), mode of inheritance: AD
• neurofibromatosis type 2 (Supportive), mode of inheritance: AD
• neurofibromatosis type 2 (Definitive), mode of inheritance: AD
• neurofibromatosis type 2 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Schwannomatosis, vestibular (Neurofibromatosis type II)	AD	Oncologic	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	Oncologic	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

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NF2 gene.

• Neurofibromatosis, type 2 (1407 variants)
• Hereditary cancer-predisposing syndrome (737 variants)
• not provided (167 variants)
• Familial meningioma (44 variants)
• not specified (37 variants)
• Schwannomatosis 1 (6 variants)
• NF2-related condition (5 variants)
• Inborn genetic diseases (4 variants)
• Schwannomatosis 1;Familial meningioma;Neurofibromatosis, type 2 (4 variants)
• Neurofibromatosis, type 2;Familial meningioma;Schwannomatosis 1 (3 variants)
• - (2 variants)
• Familial meningioma;Neurofibromatosis, type 2;Schwannomatosis 1 (2 variants)
• Meningioma (2 variants)
• Neurofibromatosis, type 2;Schwannomatosis 1;Familial meningioma (1 variants)
• Malignant tumor of breast (1 variants)
• Spindle cell sarcoma (1 variants)
• Marfanoid habitus and intellectual disability (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NF2 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			5	331	1	337
missense	1	2	643	7		653
nonsense	60	1	1			62
start loss	1		4			5
frameshift	61	6	4			71
inframe indel		1	13			14
splice donor/acceptor (+/-2bp)	39	21	3			63
splice region		1	51	57	3	112
non coding			133	189	59	381
Total	162	31	806	527	60

Variants in NF2

This is a list of pathogenic ClinVar variants found in the NF2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
22-29603597-A-G		Neurofibromatosis, type 2	Uncertain significance (Jan 12, 2018)
22-29603602-C-T		Neurofibromatosis, type 2	Uncertain significance (Jan 13, 2018)
22-29603679-C-T		Neurofibromatosis, type 2	Uncertain significance (Jun 14, 2016)
22-29603715-C-A		Neurofibromatosis, type 2	Uncertain significance (Jun 14, 2016)
22-29603731-G-T		Neurofibromatosis, type 2	Uncertain significance (Jan 13, 2018)
22-29603753-C-G		Neurofibromatosis, type 2	Benign (Jan 13, 2018)
22-29603754-C-G		Neurofibromatosis, type 2	Benign (Jan 13, 2018)
22-29603795-C-A		Neurofibromatosis, type 2	Benign (Jun 19, 2018)
22-29603836-C-T		Neurofibromatosis, type 2	Uncertain significance (Jan 12, 2018)
22-29603853-TG-T		Neurofibromatosis, type 2	Uncertain significance (Jul 02, 2018)
22-29603889-G-C		Neurofibromatosis, type 2	Benign (Jun 24, 2018)
22-29603933-AG-A		Neurofibromatosis, type 2	Uncertain significance (Dec 26, 2023)
22-29603981-G-A		not specified • Neurofibromatosis, type 2	Benign/Likely benign (Jul 07, 2023)
22-29603994-G-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 22, 2023)
22-29603994-G-T		Hereditary cancer-predisposing syndrome • Neurofibromatosis, type 2	Uncertain significance (Aug 15, 2023)
22-29603995-CG-AA		Hereditary cancer-predisposing syndrome	Uncertain significance (Dec 14, 2021)
22-29603995-CGCCATGGCCGGG-C		Neurofibromatosis, type 2	Uncertain significance (Jul 20, 2023)
22-29603998-C-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Oct 19, 2020)
22-29603999-A-G		Neurofibromatosis, type 2	Conflicting classifications of pathogenicity (Mar 26, 2024)
22-29604000-T-C			Uncertain significance (May 08, 2023)
22-29604001-G-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Nov 17, 2022)
22-29604002-G-T		Neurofibromatosis, type 2 • Familial meningioma • Schwannomatosis 1	Uncertain significance (Apr 27, 2019)
22-29604004-C-T		Neurofibromatosis, type 2	Likely benign (Jun 05, 2019)
22-29604004-CG-C		Neurofibromatosis, type 2	Pathogenic (Apr 10, 2022)
22-29604005-G-C		Familial meningioma • Neurofibromatosis, type 2	Uncertain significance (Jan 12, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NF2	protein_coding	protein_coding	ENST00000338641	16	95043

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000443	125744	0	3	125747	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.29	208	324	0.642	0.0000193	3952
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000615	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;miR-targeted genes in squamous cell - TarBase;Ectoderm Differentiation;Signal Transduction;Fcgamma receptor (FCGR) dependent phagocytosis;Innate Immune System;Immune System;RHO GTPases activate PAKs;RHO GTPase Effectors;Signaling by Rho GTPases;Regulation of actin dynamics for phagocytic cup formation;ErbB2/ErbB3 signaling events (Consensus)

Recessive Scores

• pRec: 0.357

Intolerance Scores

• loftool: 0.00841
• rvis_EVS: -0.87
• rvis_percentile_EVS: 10.65

Haploinsufficiency Scores

• pHI: 0.975
• hipred: Y
• hipred_score: 0.825
• ghis: 0.651

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.688

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nf2
• 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); hearing/vestibular/ear phenotype; vision/eye phenotype; immune system phenotype; renal/urinary system phenotype; skeleton phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system 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); reproductive system phenotype; endocrine/exocrine gland phenotype; neoplasm; craniofacial phenotype; homeostasis/metabolism 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: nf2b
• Affected structure: hepatocyte
• Phenotype tag: abnormal
• Phenotype quality: increased distance

Gene ontology

• Biological process: mesoderm formation;negative regulation of cell-matrix adhesion;negative regulation of protein kinase activity;ectoderm development;negative regulation of cell population proliferation;Schwann cell proliferation;regulation of gliogenesis;hippocampus development;negative regulation of cell-cell adhesion;actin cytoskeleton organization;negative regulation of cell migration;regulation of protein stability;regulation of hippo signaling;odontogenesis of dentin-containing tooth;negative regulation of tyrosine phosphorylation of STAT protein;regulation of apoptotic process;negative regulation of MAPK cascade;cell-cell junction organization;positive regulation of cell differentiation;negative regulation of JAK-STAT cascade;positive regulation of stress fiber assembly;regulation of cell cycle;lens fiber cell differentiation;regulation of stem cell proliferation;regulation of protein localization to nucleus;regulation of neural precursor cell proliferation
• Cellular component: nucleus;nucleolus;cytoplasm;early endosome;cytosol;cytoskeleton;plasma membrane;adherens junction;membrane;lamellipodium;cortical actin cytoskeleton;filopodium membrane;cleavage furrow;ruffle membrane;neuron projection;cell body;apical part of cell;perinuclear region of cytoplasm
• Molecular function: actin binding;protein binding