chr8-89935609-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_002485.5(NBN):c.2238C>A(p.Tyr746Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,398 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). Synonymous variant affecting the same amino acid position (i.e. Y746Y) has been classified as Likely benign.
Frequency
Consequence
NM_002485.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.2238C>A | p.Tyr746Ter | stop_gained | 16/16 | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.2238C>A | p.Tyr746Ter | stop_gained | 16/16 | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250384Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135394
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455398Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 724230
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2022 | This sequence change creates a premature translational stop signal (p.Tyr746*) in the NBN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the NBN protein. This variant is present in population databases (rs751570713, gnomAD 0.0009%). 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: 480044). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Aplastic anemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 16, 2023 | The p.Y746* variant (also known as c.2238C>A), located in coding exon 16 of the NBN gene, results from a C to A substitution at nucleotide position 2238. This changes the amino acid from a tyrosine to a stop codon within coding exon 16. One study detected this mutation in 0/3030 pancreatic cancer cases and 1/123136 population controls (Hu C et al. JAMA, 2018 06;319:2401-2409). This stop codon occurs at the 3' terminus of NBN, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 9 amino acids of the protein. However, the truncation occurs in an ATM binding domain, and upstream of a nuclear localization signal. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2017 | This variant is denoted NBN c.2238C>A at the cDNA level and p.Tyr746Ter (Y746X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA). This variant has not, to our knowledge, been reported in the literature. NBN Tyr746Ter results in the loss of 9 amino acids at the end of the protein, which might affect normal function. However, due to the location of the newly created nonsense codon in the last exon, the transcript is not expected to undergo nonsense-mediated decay and could therefore encode a truncated protein that retains some normal function. The deleted residues are located in the region of interaction with ATM (Damiola 2014). NBN Tyr746Ter was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Based on currently available evidence, it is unclear whether NBN Tyr746Ter is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at