22-29661312-C-G

Variant names:

• chr22-29661312-C-G
• rs765223726
• NM_000268.4:c.783C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000268.4(NF2):​c.783C>G​(p.Ile261Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I261I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NF2 NM_000268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

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.783C>G	p.Ile261Met	missense	Exon 8 of 16	NP_000259.1
	NF2	NM_001407066.1		c.783C>G	p.Ile261Met	missense	Exon 8 of 17	NP_001393995.1
	NF2	NM_016418.5		c.783C>G	p.Ile261Met	missense	Exon 8 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.783C>G	p.Ile261Met	missense	Exon 8 of 16	ENSP00000344666.5
	NF2	ENST00000397789.3	TSL:1	c.783C>G	p.Ile261Met	missense	Exon 8 of 17	ENSP00000380891.3
	NF2	ENST00000403999.7	TSL:1	c.783C>G	p.Ile261Met	missense	Exon 8 of 16	ENSP00000384797.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000170 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

May 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I261M variant (also known as c.783C>G), located in coding exon 8 of the NF2 gene, results from a C to G substitution at nucleotide position 783. The isoleucine at codon 261 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.85		Gain of catalytic residue at I261 (P = 0.0194)
MVP		0.96
MPC		1.6
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.91
gMVP		0.76
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs765223726; hg19: chr22-30057301;