ClinVar Miner

Submissions for variant NM_005198.5(CHKB):c.224+5G>C

gnomAD frequency: 0.00002  dbSNP: rs765251030
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480811 SCV000573548 likely pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing The c.224+5 G>C variant in the CHKB gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.224+5 G>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.224+5 G>C destroys the natural splice donor site for intron 1 which may lead to abnormal gene splicing. This variant occurs at a position that is conserved across species. In summary, we interpret c.224+5 G>C to be a likely pathogenic variant. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown.
Labcorp Genetics (formerly Invitae), Labcorp RCV001245358 SCV001418641 uncertain significance Megaconial type congenital muscular dystrophy 2023-08-28 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the CHKB gene. It does not directly change the encoded amino acid sequence of the CHKB protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs765251030, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CHKB-related conditions. ClinVar contains an entry for this variant (Variation ID: 423804). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Undiagnosed Diseases Network, NIH RCV001245358 SCV001432144 uncertain significance Megaconial type congenital muscular dystrophy 2018-03-06 criteria provided, single submitter clinical testing

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