ClinVar Miner

Submissions for variant NM_020361.5(CPA6):c.1237C>T (p.Leu413Phe)

gnomAD frequency: 0.00266  dbSNP: rs142597675
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000174147 SCV000225394 likely benign not specified 2014-12-02 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000513972 SCV000610369 likely benign not provided 2017-02-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001085493 SCV001097966 benign Febrile seizures, familial, 11 2024-10-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000513972 SCV001553527 uncertain significance not provided no assertion criteria provided clinical testing The CPA6 p.Leu413Phe variant was not identified in the literature but was identified in dbSNP (ID: rs142597675), ClinVar (classified as likely benign by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and EGL Genetics) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 240 of 282796 chromosomes (1 homozygous) at a frequency of 0.000849 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 213 of 24962 chromosomes (freq: 0.008533), Other in 3 of 7224 chromosomes (freq: 0.000415), Latino in 13 of 35436 chromosomes (freq: 0.000367), European (non-Finnish) in 9 of 129114 chromosomes (freq: 0.00007) and South Asian in 2 of 30616 chromosomes (freq: 0.000065), but was not observed in the Ashkenazi Jewish, East Asian and European (Finnish) populations. The p.Leu413 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. However a study of CPA6 variants reported in the general population suggests that although leucine and phenylalanine are similar in size, phenylalanine is a little larger and this may displace the hydrodynamic balance of surrounding residues (Sapio_2012_PMID: 23105115). The variant occurs 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. This variant is classified as a variant of uncertain significance.

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