Submissions for variant NM_000742.4(CHRNA2):c.286A>T (p.Ile96Phe)

dbSNP: rs149615415

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186860	SCV000240431	uncertain significance	not provided	2014-06-11	criteria provided, single submitter	clinical testing	p.Ile96Phe (ATC>TTC): c.286 A>T in exon 3 of the CHRNA2 gene (NM_000742.3). A variant of unknown significance has been identified in the CHRNA2 gene. The I96F variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I96F substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, I96F is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this amino acid substitution does not occur within the transmembrane region of the protein, where the vast majority of pathogenic missense mutations have been identified in association with epilepsy (Steinlein et al., 2010). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001323890	SCV001514825	uncertain significance	Autosomal dominant nocturnal frontal lobe epilepsy	2022-06-20	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHRNA2 protein function. 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. ClinVar contains an entry for this variant (Variation ID: 204955). This variant has not been reported in the literature in individuals affected with CHRNA2-related conditions. This variant is present in population databases (rs149615415, gnomAD 0.007%). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 96 of the CHRNA2 protein (p.Ile96Phe).