chr22-29674891-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000268.4(NF2):c.1396C>T(p.Arg466Ter) variant causes a stop gained 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R466R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NF2
NM_000268.4 stop_gained
NM_000268.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 4.87
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 22-29674891-C-T is Pathogenic according to our data. Variant chr22-29674891-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-29674891-C-T is described in Lovd as [Pathogenic]. Variant chr22-29674891-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF2 | NM_000268.4 | c.1396C>T | p.Arg466Ter | stop_gained | 13/16 | ENST00000338641.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF2 | ENST00000338641.10 | c.1396C>T | p.Arg466Ter | stop_gained | 13/16 | 1 | NM_000268.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1422466Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 703622
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1422466
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31
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0
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703622
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurofibromatosis, type 2 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 21, 2022 | ClinVar contains an entry for this variant (Variation ID: 3295). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 2 (PMID: 7913580, 8012353, 12566519, 18033041, 18766994, 24815379, 26066488). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg466*) in the NF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF2 are known to be pathogenic (PMID: 9643284, 16983642). - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1994 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Sep 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 08, 2019 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. Damaging to protein function(s) relevant to disease mechanism. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2017 | The p.R466* pathogenic mutation (also known as c.1396C>T), located in coding exon 13 of the NF2 gene, results from a C to T substitution at nucleotide position 1396. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been reported in multiple individuals with clinical features of neurofibromatosis type 2 (MacCollin M et al. Am. J. Hum. Genet. 1994 Aug;55(2):314-20; Bourn D et al. Hum. Genet. 1995 May;95(5):572-4; Parry DM et al. Am. J. Hum. Genet. 1996 Sep;59(3):529-39; Kluwe L et al. J. Med. Genet. 2003 Feb;40(2):109-14; Grant EA et al. Ophthalmic Genet. 2008 Sep;29(3):133-8; Goutagny S et al. J. Neurooncol. 2015 Apr;122(2):313-20). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A
Vest4
ClinPred
D
GERP RS
Splicing
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Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at