NF2

Gene Facts

• HGNC Symbol: NF2 (HGNC:7773)
• HGNC Name: NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: merlin, ACN, SCH, BANF, merlin-1
• %HI: 2.2
• pLI: 1
• LOEUF: 0.19
• Cytoband: 22q12.2
• Genomic Coordinates:

  GRCh37/hg19:	chr22:29999545-30094589
  GRCh38/hg38:	chr22:29603556-29698600

• MANE Select Transcript: NM_000268.4 ENST00000338641.10
• 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. Suppress... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-35819
• ClinGen Curation ID: CCID:007548
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 09/08/2020

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• neurofibromatosis type 2

HI Evidence

• PUBMED: PMID:7913580
  MacCollin et al. (1994): Describes 33 unrelated individuals with a clinical diagnosis of NF2. Of 20 unique variants observed, 19 were predicted to result in truncated protein due to frameshift, creation of a stop codon, or interference with normal RNA splicing, including 9 different nonsense mutations.
• PUBMED: PMID:9817927
  Zucman-Rossi et al (1998): Describes 19 unrelated individuals with a clinical diagnosis of NF2, six of whom were found to have either whole-gene or intragenic deletions of the NF2 gene.
• PUBMED: PMID:11159946
  Bruder et al. (2001): Describes deletions identified by arrayCGH involving NF2 identified in 17 additional previously unreported individuals with neurofibromatosis type 2. These cases include both intragenic deletions and larger deletions involving other genes.

• HI Evidence Comments: Loss-of-function mutations in NF2 have been associated with neurofibromatosis type 2. Of note, larger deletions encompassing the NF2 gene (in addition to other genes) have been described in patients with neurofibromatosis type 2, developmental delays and other congenital anomalies (as in PMID: 10338003). However, it has been suggested that whole-gene or intragenic deletions involving NF2 alone are associated with a milder NF2 phenotype than individuals with other types of mutations (GeneReviews; PMID:15190457). A meta-analysis by Ahronowitz et al. (PMID:16983642）summarized over 900 NF2 pathogenic variants reported prior to the year 2006. The mutation spectrum for constitutional alternations was 39% nonsense, 27% frameshift, 25% splicing site and 7% nontruncating; The mutation spectrum for somatic alternations was 56% frameshift, 19% nonsense, 19% splice site and 0% nontruncating. Currently in ClinVar (accessed on Sept. 7 2020), there are a total of 142 NF2 pathogenic or likely pathogenic variants including 31 frameshift, 30 nonsense, 27 splicing site, 24 exonic deletion and 8 missense variants. Recently, Evans et al. (PMID:31273341) reported a high prevalence of mosaic NF2 mutations among de novo NF2 cases. Among 232 confirmed mosaic patients, there were 97 nonsense, 57 frameshift, 32 CNV, 24 splicing site and 12 nontruncating variants. Overall the vast majority of NF2 pathogenic variants are loss-of-function variants which several hundreds had been reported.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: Though intragenic duplications have been reported (as in PMID:15857181 and 15645494) in individuals with NF2, no whole-gene duplications of NF2 have been reported at this time.