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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, 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

Sel.	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	P35240-1
	NF2	NM_001407066.1		c.288_290delCTT	p.Phe96del	disruptive_inframe_deletion	Exon 3 of 17	NP_001393995.1	P35240-3
	NF2	NM_016418.5		c.288_290delCTT	p.Phe96del	disruptive_inframe_deletion	Exon 3 of 17	NP_057502.2	P35240-3

Ensembl Transcripts

Sel.	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	P35240-1
	NF2	ENST00000397789.3	TSL:1	c.288_290delCTT	p.Phe96del	disruptive_inframe_deletion	Exon 3 of 17	ENSP00000380891.3	P35240-3
	NF2	ENST00000403999.7	TSL:1	c.288_290delCTT	p.Phe96del	disruptive_inframe_deletion	Exon 3 of 16	ENSP00000384797.3	P35240-3

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Neurofibromatosis, type 2 (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	SMARCB1-related schwannomatosis (1)

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;