ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.897-2A>T (rs864622090)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222760 SCV000274462 likely pathogenic Hereditary cancer-predisposing syndrome 2017-06-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Integrated Genetics/Laboratory Corporation of America RCV000204744 SCV000697982 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2016-12-05 criteria provided, single submitter clinical testing Variant summary: The NBN c.897-2A>T variant involves the alteration of a highly conserved nucleotide. 5/5 splice prediction tools via Alamut suggest a loss of consensus acceptor site and creation of a new acceptor splice site within exon8, which will lead to an alternative transcript resulting in a loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. However the functional studies confirming these predictions are yet to be conducted. This variant is absent from the general population (ExAC data). The variant of interest has not, to our knowledge, been reported in affected individuals via publications but was cited as Likely Pathogenic by reputable databases/clinical diagnostic laboratories. Taken together, this variant is classified as Likely Pathogenic.
Invitae RCV000204744 SCV000259306 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2018-08-08 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 of the NBN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 219440). 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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