Submissions for variant NM_020361.5(CPA6):c.275G>A (p.Arg92Gln)

gnomAD frequency: 0.00004  dbSNP: rs147475942

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001233051	SCV001405629	uncertain significance	Febrile seizures, familial, 11	2022-07-26	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs147475942, gnomAD 0.01%). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 959664). This variant has not been reported in the literature in individuals affected with CPA6-related conditions. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 92 of the CPA6 protein (p.Arg92Gln).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356737	SCV001551990	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CPA6 p.Arg92Gln variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs147475942) and in control databases in 7 of 281766 chromosomes at a frequency of 0.000025 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 3 of 30358 chromosomes (freq: 0.000099), African in 2 of 24926 chromosomes (freq: 0.00008), Latino in 1 of 35064 chromosomes (freq: 0.000029) and European (non-Finnish) in 1 of 128916 chromosomes (freq: 0.000008), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) or Other populations. The p.Arg92 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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.