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: CFTR c.2684G>A (p.Ser895Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251266 control chromosomes, predominantly at a frequency of 0.0048 within the East Asian subpopulation in the gnomAD database. The variant occurs with an even higher frequency in the Other East-Asian (presumably mostly Chinese) sub population (i.e. with a frequency of 0.006), and although this frequency is not higher than the estimated maximum expected for a pathogenic variant in CFTR causing Cystic Fibrosis (CF) in the Caucasian population (0.013), however, in a recent study the estimated Chinese CF prevalence was reported to be about 40x lower than the prevalence in Caucasians (Ni_2022), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.2684G>A, has been reported in the literature in four Chinese individuals affected with Cystic Fibrosis (Wu_2000, Alper_2003, Wang_2019, Yang_2021), however, in all of these patients the variant occurred in cis with a pathogenic variant (c.2083dupG (p.Glu695fs)), and all patients also carried a pathogenic variant (c.1898+5G>T) in trans, therefore these co-occurrences with other pathogenic variants provide supporting evidence for a benign role. The variant was also reported in two Chinese patients affected with congenital absence of vas deferens (CAVD; Luo_2021), however one of these patients also carried the variant c.2083dupG (p.Glu695fs) which was described earlier in cis in four Chinese CF patients, while the other patient carried two (potentially) pathogenic variants which could explain the phenotype (though the phase was not specified). In addition, the variant was published in heterozygous state in individuals affected with pancreatitis (Chang_2015, Palermo_2016) and bronchiectasis (Guan_2018), but was also found in healthy subject with a similar frequency (Guan_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=5) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.

The CFTR c.2684G>A variant is predicted to result in the amino acid substitution p.Ser895Asn. This variant has been reported in patients with pancreatitis (Table 3, Palermo et al. 2016. PubMed ID: 27171515; Chang et al. 2007. PubMed ID: 17539902; Chang et al. 2015. PubMed ID: 25869325) and bronchiectasis (Guan et al. 2018. PubMed ID: 29997923). The patient discussed in Guan et al. was also homozygous for a different variant in CFTR. This variant is reported in 0.46% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117243612-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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.

The allele frequency of this variant c.2684G>A (p.Ser895Asn) is 0.0026 in East Asian of gnomAD and 0.003 in East Asian in 1000 Genomes. The variant is predicted to be tolerated by both SIFT or PolyPhen2. For these reasons, this variant has been classified as Likely Benign.

Observed in individuals with cystic fibrosis, bronchiectasis, congenital absence of the vas deferens, or pancreatitis, with and without additional CFTR variants reported, but familial segregation information and additional clinical information was not included (PMID: 12874665, 29997923, 34673937, 30811104, 32777524, 27171515, 28502372); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27143075, 26199320, 34276759, 27171515, 25869325, 29997923, 32777524, 32508047, 15905293, 34673937, 30811104, 28608624, 28502372, 31423445, 30558651, 30379828, 27717243, 29216686, 25580864, 17539902, 35313924, 34842611, 37313453, 27081564, 12874665, 36437957, 35858753, 10925568)