22-29661242-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000268.4(NF2):c.713C>T(p.Ala238Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,126 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A238S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000268.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF2 | NM_000268.4 | c.713C>T | p.Ala238Val | missense_variant | 8/16 | ENST00000338641.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF2 | ENST00000338641.10 | c.713C>T | p.Ala238Val | missense_variant | 8/16 | 1 | NM_000268.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152254Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251472Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135910
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727234
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152254Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74400
ClinVar
Submissions by phenotype
Neurofibromatosis, type 2 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 27, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 238 of the NF2 protein (p.Ala238Val). This variant is present in population databases (rs761195572, gnomAD 0.0009%). 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: 578288). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 28, 2023 | This missense variant replaces alanine with valine at codon 238 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 one individual affected with hepatocellular carcinoma (PMID: 22081132). This variant has been identified in 1/251472 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 provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22081132, 11756419, 16324214) - |
Familial meningioma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 28, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2023 | The p.A238V variant (also known as c.713C>T), located in coding exon 8 of the NF2 gene, results from a C to T substitution at nucleotide position 713. The alanine at codon 238 is replaced by valine, an amino acid with similar properties. This alteration has been reported in an individual with hepatocellular carcinoma (Yoo NJ et al. Pathology, 2012 Jan;44:29-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at