ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1911_1914+1del (rs1554556880)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000582963 SCV000690683 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-08 criteria provided, single submitter clinical testing This variant deletes 5 nucleotides at the exon 12/intron 12 junction of the NBN gene. This variant may have a significant impact on RNA splicing and may cause the skipping of exon 12, which would result in an in-frame deletion of 23 amino acids. However, this prediction has not been confirmed in published RNA studies. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). While this variant is expected to disrupt the splice donor site of intron 12, the impact on the encoded protein has not been determined. Conflicting classifications have been reported for variants affecting the same splice site (ClinVar variation ID: 492105, 802418). In addition, to our knowledge, there is no experimental or clinical evidence indicating that exon 12 is associated with critical NBN function or NBN-related diseases. The available evidence is insufficient to determine the role of this variant in disease conclusively based on the ACMG guideline (PMID: 30192042). Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV000804835 SCV000944768 likely pathogenic Microcephaly, normal intelligence and immunodeficiency 2019-12-27 criteria provided, single submitter clinical testing This variant is a deletion of the genomic region encompassing part of exon 12 (c.1911_1914+1del) of the NBN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 492105). 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.
Ambry Genetics RCV000582963 SCV001174279 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-06 criteria provided, single submitter clinical testing The c.1911_1914+1delATCTG intronic variant results from a deletion of 5 nucleotides after coding exon 12 of the NBN gene. This nucleotide region is generally well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.