rs141629512
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_000268.4(NF2):āc.613A>Gā(p.Met205Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M205T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000268.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF2 | NM_000268.4 | c.613A>G | p.Met205Val | missense_variant | 7/16 | ENST00000338641.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF2 | ENST00000338641.10 | c.613A>G | p.Met205Val | missense_variant | 7/16 | 1 | NM_000268.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152204Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000795 AC: 20AN: 251478Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135912
GnomAD4 exome AF: 0.000333 AC: 487AN: 1461840Hom.: 0 Cov.: 31 AF XY: 0.000338 AC XY: 246AN XY: 727224
GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152204Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13AN XY: 74354
ClinVar
Submissions by phenotype
Neurofibromatosis, type 2 Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces methionine with valine at codon 205 of the NF2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with multiple meningiomas or Neurofibromatosis type 2 (PMID: 15635074, 26073919). This variant has been identified in 24/282888 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 23, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 or 3 probands - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 12, 2023 | Variant summary: NF2 c.613A>G (p.Met205Val) results in a conservative amino acid change located in the FERM domain (IPR000299) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 282888 control chromosomes (gnomAD), predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF2 causing Neurofibromatosis Type 2 phenotype (1.9e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, two as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 02, 2023 | See Variant Classification Assertion Criteria. - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 21, 2021 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at