22-29678299-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000268.4(NF2):​c.1550T>C​(p.Leu517Pro) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

NF2
NM_000268.4 missense

Scores

10
7
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 6.21
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.869
PP5
Variant 22-29678299-T-C is Pathogenic according to our data. Variant chr22-29678299-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547709.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NF2NM_000268.4 linkc.1550T>C p.Leu517Pro missense_variant Exon 14 of 16 ENST00000338641.10 NP_000259.1 P35240-1A0A024R1J8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NF2ENST00000338641.10 linkc.1550T>C p.Leu517Pro missense_variant Exon 14 of 16 1 NM_000268.4 ENSP00000344666.5 P35240-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Neurofibromatosis, type 2 Pathogenic:2Uncertain:1
Jan 13, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 517 of the NF2 protein (p.Leu517Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 547709). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF2 protein function. Experimental studies have shown that this missense change affects NF2 function (PMID: 26045165). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nov 07, 2021
Genome-Nilou Lab
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
Dec 16, 2019
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: fails to bind Lats1 and results in decreased phosphor-YAP (Li et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16983642, 26045165) -

Hereditary cancer-predisposing syndrome Pathogenic:1
Jan 27, 2019
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.L517P variant (also known as c.1550T>C), located in coding exon 14 of the NF2 gene, results from a T to C substitution at nucleotide position 1550. The leucine at codon 517 is replaced by proline, an amino acid with similar properties. This alteration was seen in a patient with bilateral vestibular schwannomas (Ahronowitz I et al. Hum. Mutat., 2007 Jan;28:1-12). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.86
D;.;.;.;.;.;.;.;.
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;D;D;.;.;D;.;D;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.44
D
MutationAssessor
Uncertain
2.2
M;.;.;M;.;.;M;.;M
PrimateAI
Pathogenic
0.92
D
PROVEAN
Uncertain
-4.3
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D;D
Sift4G
Benign
0.073
T;T;T;T;T;T;T;D;T
Polyphen
0.38
B;P;B;B;B;B;B;B;B
Vest4
0.76
MutPred
0.76
Loss of stability (P = 0.0311);.;.;Loss of stability (P = 0.0311);.;.;Loss of stability (P = 0.0311);.;Loss of stability (P = 0.0311);
MVP
0.99
MPC
1.7
ClinPred
0.99
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.93
gMVP
0.78

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1556002568; hg19: chr22-30074288; API