ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.23847+2T>C (rs545937015)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000416472 SCV000640726 likely pathogenic Nemaline myopathy 2 2017-10-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 166 of the NEB 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 (rs545937015, ExAC 0.01%). This variant has not been reported in the literature in individuals with NEB-related disease. ClinVar contains an entry for this variant (Variation ID: 375408). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). 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.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000416472 SCV000494237 likely pathogenic Nemaline myopathy 2 2016-06-27 criteria provided, single submitter clinical testing The c.23847+2T>C splice variant in the NEB gene has not been previously reported in patients and this variant is absent (1000 Genomes; Exome Sequencing Project) or reported at low frequency in the population databases (ExAC = 0.01%; only 2 alleles). Splice-site, nonsense, and frameshift variants have been described in the NEB gene in multiple affected individuals (including nonsense and frameshift variants downstream of this variant) and thus, loss of function is a known mechanism of disease (GeneReviews: North and Ryan, 2015). Multiple in silico algorithms show high evolutionary conservation (CADD = 18.14; GERP=5.48), and in silico splicing algorithms predict this variant will cause altered splicing (Human Splice Finder=Broken WT Donor Site; SPIDEX=-3.228). Therefore, this collective evidence supports the classification of the c.23847+2T>C variant as a Likely pathogenic variant for Nemaline Myopathy 2. We have confirmed this finding in our laboratory using Sanger sequencing.

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