rs1556002511

chr22-29678233-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000268.4(NF2):c.1484T>G(p.Ile495Arg) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I495V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF2 NM_000268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1723068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF2	NM_000268.4	c.1484T>G	p.Ile495Arg	missense_variant	14/16	ENST00000338641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF2	ENST00000338641.10	c.1484T>G	p.Ile495Arg	missense_variant	14/16	1	NM_000268.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurofibromatosis, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 30, 2017

In summary, this variant has uncertain impact on NF2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a NF2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with arginine at codon 495 of the NF2 protein (p.Ile495Arg). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	21
Dann	Benign	0.93
DEOGEN2	Uncertain	0.57	D;.;.;.;.;.;.;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.030
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;T;.;.;T;.;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.4	L;.;.;L;.;.;L;.;L
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.54	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T;T;T;T;T
Polyphen		0.036	B;B;B;B;B;B;B;B;B
Vest4		0.26
MutPred		0.48		Gain of methylation at I495 (P = 0.0461);.;.;Gain of methylation at I495 (P = 0.0461);.;.;Gain of methylation at I495 (P = 0.0461);.;Gain of methylation at I495 (P = 0.0461);
MVP		0.78
MPC		1.4
ClinPred		0.57	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556002511; hg19: chr22-30074222;