ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1914+10G>A (rs577706448)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000192466 SCV000170643 benign not specified 2014-02-25 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.
Genetic Services Laboratory, University of Chicago RCV000192466 SCV000248135 uncertain significance not specified 2014-12-05 criteria provided, single submitter clinical testing
Invitae RCV000232925 SCV000287459 benign Microcephaly, normal intelligence and immunodeficiency 2020-12-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000581136 SCV000685742 likely benign Hereditary cancer-predisposing syndrome 2015-04-29 criteria provided, single submitter clinical testing
Counsyl RCV000232925 SCV000794667 likely benign Microcephaly, normal intelligence and immunodeficiency 2017-10-11 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679456 SCV000806422 likely benign not provided 2017-03-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679456 SCV001134503 benign not provided 2019-03-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000192466 SCV001337976 likely benign not specified 2020-01-23 criteria provided, single submitter clinical testing Variant summary: NBN c.1914+10G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00027 in 220710 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (0.00027 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1914+10G>A in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc. RCV000232925 SCV001455018 likely benign Microcephaly, normal intelligence and immunodeficiency 2019-11-11 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357262 SCV001552681 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The NBN c.1914+10G>A variant was not identified in the literature. The variant was identified in dbSNP (rs577706448) as “with other allele”, ClinVar (classified as likely benign by Color, Counsyl and Prevention Genetics; as benign by Invitae and GeneDx and as uncertain significance by University of Chicago) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 59 of 220,710 chromosomes (1 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 34 of 27,638 chromosomes (freq: 0.001), Latino in 15 of 32,818 chromosomes (freq: 0.0005), Other in 1 of 5498 chromosomes (freq: 0.0002), African in 1 of 13,392 chromosomes (freq: 0.00008), European in 7 of 94,896 chromosomes (freq: 0.00007) and Finnish in 1 of 20,126 chromosomes (freq: 0.00005), while the variant was not observed in the Ashkenazi Jewish or East Asian populations. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000679456 SCV001932549 likely benign not provided no assertion criteria provided clinical testing

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