ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.171+4T>C (rs587782290)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131170 SCV000186116 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Invitae RCV000205676 SCV000259796 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-12-11 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the NBN gene. It does not directly change the encoded amino acid sequence of the NBN protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs587782290, ExAC 0.01%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 142185). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000432642 SCV000518617 likely benign not specified 2016-02-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000590607 SCV000697950 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing Variant summary: The NBN c.171+4T>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict strengthen effect on a canonical splicing donor site, and ESEfinder predicts change of binding site for SR055. However, these predictions have yet to be confirmed by functional studies. This variant was found in 3/121362 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic NBN variant (0.0025). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000205676 SCV000789324 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2017-01-25 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000590607 SCV000806416 likely benign not provided 2017-03-17 criteria provided, single submitter clinical testing
Mendelics RCV000205676 SCV000838319 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000131170 SCV000911289 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing

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