chr22-29658251-A-G
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PP3_ModerateBP6BS1BS2
The ENST00000338641.10(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
Consequence
ENST00000338641.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF2 | NM_000268.4 | c.662A>G | p.Tyr221Cys | missense_variant | 7/16 | ENST00000338641.10 | NP_000259.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NF2 | ENST00000338641.10 | c.662A>G | p.Tyr221Cys | missense_variant | 7/16 | 1 | NM_000268.4 | ENSP00000344666 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251478Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135912
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727234
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152162Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74326
ClinVar
Submissions by phenotype
Neurofibromatosis, type 2 Uncertain:3
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 | Jun 11, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at