Submissions for variant NM_001164508.2(NEB):c.23742+2T>C

gnomAD frequency: 0.00006  dbSNP: rs545937015

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000416472	SCV000640726	likely pathogenic	Nemaline myopathy 2	2024-01-31	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. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs545937015, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. 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. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195395	SCV001365744	uncertain significance	not specified	2019-07-25	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The c.23847+2T>C variant in NEB has not been previously reported in individuals with myopathy but has been identified in 0.008% (10/128308) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID: 375408). This variant occurs within the canonical splice site (+/- 1,2), but splicing predictors do not predict a significant change in splicing and the exons surrounding this variant are in-frame. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PMS2
Revvity Omics, Revvity	RCV001782898	SCV002017914	likely pathogenic	not provided	2019-11-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476005	SCV004200211	likely pathogenic	Arthrogryposis multiplex congenita 6	2024-02-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001782898	SCV005396447	likely pathogenic	not provided	2024-05-09	criteria provided, single submitter	clinical testing	Reported as a single heterozygous variant in an individual undergoing preconception carrier screening (PMID: 29754767); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 31589614, 29754767)
Natera, Inc.	RCV000416472	SCV001459172	likely pathogenic	Nemaline myopathy 2	2020-09-16	no assertion criteria provided	clinical testing