ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.38-2A>G (rs771475965)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000775396 SCV000909729 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000775396 SCV001182831 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-26 criteria provided, single submitter clinical testing The c.38-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 2 in the NBN gene. This nucleotide position is highly conserved in available vertebrate species. The BDGP splice prediction software does not produce a reliable prediction for the nearby native splice acceptor site, the ESEfinder splice prediction software predicts that this alteration will abolish the native splice acceptor site, and the Human Splicing Finder (HSF) splice prediction tool predicts that this alteration will abolish the native splice acceptor site; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Invitae RCV001067027 SCV001232056 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2019-01-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 of the NBN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs771475965, ExAC 0.002%). This variant has not been reported in the literature in individuals with NBN-related conditions. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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