ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Variant summary: NCF2 c.113G>A (p.Arg38Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 251480 control chromosomes, predominantly at a frequency of 0.002 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in NCF2 causing Chronic Granulomatous Disease phenotype (0.00061), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.113G>A has been reported in the literature as associated with very early onset inflammatory bowel disease (IBD) and shown to reduce binding to RAC2 (example, Muise_2012). In recent reports, it continues to be cited among reported polymorphisms in the NCF2 gene (example, Roos_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Chronic Granulomatous Disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, due to lack of penetrant association with inherited recessive Chronic Granulomatous Disease, the variant was classified as likely benign.

BS1, BS2, PS3_moderate, PS4_moderate

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).