Submissions for variant NM_000742.4(CHRNA2):c.1464G>A (p.Ser488=)

gnomAD frequency: 0.00005  dbSNP: rs796052305

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186881	SCV000240452	uncertain significance	not provided	2012-08-31	criteria provided, single submitter	clinical testing	p.Ser488Ser (TCG>TCA):c.1464 G>A in exon 6 of the CHRNA2 gene (NM_000742.3). The c.1464 G>A nucleotide substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project did not identify c.1464 G>A in approximately 6500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The c.1464 G>A substitution alters the last nucleotide position in exon 6, and multiple in silico models predict that it may damage or even destroy donor site the natural splice donor site at the exon 6/intron 6 boundary, possibly leading to abnormal splicing. However, in the absence of RNA/functional studies, the actual effect of the c.1464 G>A sequence change in vivo is unknown. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548543	SCV000658049	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change affects codon 488 of the CHRNA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CHRNA2 protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (rs796052305, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CHRNA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 204975). 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.
Athena Diagnostics	RCV000186881	SCV001475773	uncertain significance	not provided	2020-03-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002516980	SCV003689745	likely benign	Inborn genetic diseases	2022-03-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.