rs121434260
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM4_SupportingPP5
The NM_000268.4(NF2):c.288_290delCTT(p.Phe96del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 31)
Consequence
NF2
NM_000268.4 disruptive_inframe_deletion
NM_000268.4 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.92
Genes affected
NF2 (HGNC:7773): (NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor) 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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a domain FERM (size 289) in uniprot entity MERL_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_000268.4
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000268.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 22-29639133-ACTT-A is Pathogenic according to our data. Variant chr22-29639133-ACTT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3288.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF2 | NM_000268.4 | c.288_290delCTT | p.Phe96del | disruptive_inframe_deletion | 3/16 | ENST00000338641.10 | NP_000259.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neurofibromatosis, type 2 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Swedish Neurofibromatosis Center, Swedish Medical Center | Feb 24, 2020 | PM1, PM2, PM4, PP3,PP5, PP4 - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1994 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2024 | The c.288_290delCTT variant (also known as p.F96del) is located in coding exon 3 of the NF2 gene. This variant results from an in-frame CTT deletion at nucleotide positions 288 to 290. This results in the in-frame deletion of a phenylalanine at codon 96. This variant has been reported in individuals with features of NF2-related schwannomatosis (Cordeiro NJ et al. Dev Med Child Neurol, 2006 Jan;48:58-9; Henson JW et al. Neurol Genet, 2020 Aug;6:e446). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear. - |
SMARCB1-related schwannomatosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jul 24, 2019 | - - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at