rs786203225
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_002485.5(NBN):c.1816G>A(p.Glu606Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E606E) has been classified as Likely benign.
Frequency
Consequence
NM_002485.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.1816G>A | p.Glu606Lys | missense_variant | 11/16 | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.1816G>A | p.Glu606Lys | missense_variant | 11/16 | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250860Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135630
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460222Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 726544
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 606 of the NBN protein (p.Glu606Lys). This variant is present in population databases (rs774324419, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 186796). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 19, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 03, 2017 | Variant summary: The c.1816G>A (p.Glu606Lys) in NBN gene is a missense variant involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome, however no functional studies supporting these predictions were published at the time of evaluation. The variant is present at a low frequencies in the control population datasets of ExAC and gnomAD (8.24e-06; 1/121362 and 2/245612 chrs tested, respectively). These frequencies do not exceed the maximal expected allele frequency for a disease causing allele in NBN gene (0.000125). To our knowledge, the variant has not been reported in affected individuals via published reports, but is cited as VUS by reputable databases/clinical laboratories. Taken together, the variant was classified as VUS, until new information becomes available. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 31, 2023 | This alteration is classified as likely 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