22-29658251-A-G
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PP3_ModerateBP6BS1BS2
The NM_000268.4(NF2):āc.662A>Gā(p.Tyr221Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: š 0.000039 ( 0 hom., cov: 31)
Exomes š: 0.0000021 ( 0 hom. )
Consequence
NF2
NM_000268.4 missense
NM_000268.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 9.30
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000268.4
PP3
MetaRNN computational evidence supports a deleterious effect, 0.879
BP6
Variant 22-29658251-A-G is Benign according to our data. Variant chr22-29658251-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 572959.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000394 (6/152162) while in subpopulation AFR AF= 0.000145 (6/41434). AF 95% confidence interval is 0.0000628. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF2 | NM_000268.4 | c.662A>G | p.Tyr221Cys | missense_variant | 7/16 | ENST00000338641.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF2 | ENST00000338641.10 | c.662A>G | p.Tyr221Cys | missense_variant | 7/16 | 1 | NM_000268.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251478Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135912
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727234
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74326
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neurofibromatosis, type 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2023 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF2 protein function. 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. ClinVar contains an entry for this variant (Variation ID: 572959). This missense change has been observed in individual(s) with breast cancer (PMID: 29625052). This variant is present in population databases (rs746025177, gnomAD 0.02%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 221 of the NF2 protein (p.Tyr221Cys). - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 01, 2022 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;.;.;D;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;.;H;.;.;H;.;H
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D
Polyphen
D;.;D;D;D;D;D;D;D
Vest4
MutPred
Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);.;.;Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at