rs121434260

Variant names:

• chr22-29639133-ACTT-A
• rs121434260
• NM_000268.4:c.288_290delCTT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

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). Synonymous variant affecting the same amino acid position (i.e. F96F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NF2 NM_000268.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 7.92
• Publications: 3 publications found

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]

NF2 Gene-Disease associations (from GenCC):

• NF2-related schwannomatosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• familial meningioma

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• 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 VariationId is 3288.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000268.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	NM_000268.4	MANE Select	c.288_290delCTT	p.Phe96del	disruptive_inframe_deletion	Exon 3 of 16	NP_000259.1
	NF2	NM_001407066.1		c.288_290delCTT	p.Phe96del	disruptive_inframe_deletion	Exon 3 of 17	NP_001393995.1
	NF2	NM_016418.5		c.288_290delCTT	p.Phe96del	disruptive_inframe_deletion	Exon 3 of 17	NP_057502.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF2	ENST00000338641.10	TSL:1 MANE Select	c.288_290delCTT	p.Phe96del	disruptive_inframe_deletion	Exon 3 of 16	ENSP00000344666.5
	NF2	ENST00000397789.3	TSL:1	c.288_290delCTT	p.Phe96del	disruptive_inframe_deletion	Exon 3 of 17	ENSP00000380891.3
	NF2	ENST00000403999.7	TSL:1	c.288_290delCTT	p.Phe96del	disruptive_inframe_deletion	Exon 3 of 16	ENSP00000384797.3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 2 Pathogenic:2

Feb 24, 2020

Swedish Neurofibromatosis Center, Swedish Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PM4, PP3,PP5, PP4

Aug 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 24, 2019

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121434260; hg19: chr22-30035122;