ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.22695+2T>C (rs200449517)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521210 SCV000619698 likely pathogenic not provided 2017-08-11 criteria provided, single submitter clinical testing The c.22695+2T>C pathogenic variant in the NEB gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 155. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.22695+2T>C variant is observed in 14/66506 (0.02%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). We interpret c.22695+2T>C as a likely pathogenic variant.
Counsyl RCV000666422 SCV000790711 likely pathogenic Nemaline myopathy 2 2017-04-05 criteria provided, single submitter clinical testing
Invitae RCV000666422 SCV000830524 likely pathogenic Nemaline myopathy 2 2019-11-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 155 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 (rs200449517, ExAC 0.02%). This variant has not been reported in the literature in individuals with NEB-related disease. ClinVar contains an entry for this variant (Variation ID: 451052). 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.
Illumina Clinical Services Laboratory,Illumina RCV000666422 SCV000915864 uncertain significance Nemaline myopathy 2 2018-10-30 criteria provided, single submitter clinical testing The NEB c.17487+2T>C variant, which corresponds to c.22695+2T>C in the transcript NM_001271208.1, occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found through this search. The c.17487+2T>C variant is reported at a frequency of 0.000211 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the potential impact of splice variants and the lack of clarifying evidence, the c.17487+2T>C variant is classified as of uncertain significance but suspicious for pathogenicity for nemaline myopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000521210 SCV001152434 likely pathogenic not provided 2017-09-01 criteria provided, single submitter clinical testing

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