chr8-89953686-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_002485.5(NBN):c.1403G>A(p.Arg468Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 151,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R468G) has been classified as Uncertain significance.
Frequency
Consequence
NM_002485.5 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 |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.1403G>A | p.Arg468Lys | missense_variant | 11/16 | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.1403G>A | p.Arg468Lys | missense_variant | 11/16 | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151914Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000820 AC: 2AN: 244020Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 132152
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1456108Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 724390
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151914Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74186
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 25, 2023 | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 468 of the NBN protein (p.Arg468Lys). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 411762). This variant has not been reported in the literature in individuals affected with NBN-related conditions. This variant is present in population databases (rs781213350, gnomAD 0.01%). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 28, 2024 | The p.R468K variant (also known as c.1403G>A), located in coding exon 11 of the NBN gene, results from a G to A substitution at nucleotide position 1403. The arginine at codon 468 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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