Submissions for variant NM_000492.4(CFTR):c.*2G>A

gnomAD frequency: 0.00056  dbSNP: rs150914702

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000176720	SCV000228426	uncertain significance	not provided	2017-04-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000176720	SCV001160027	uncertain significance	not provided	2023-11-27	criteria provided, single submitter	clinical testing	The CFTR c.*2G>A variant (rs150914702), also known as c.4575+2G>A or 4443+2G>A, is reported in the literature in multiple individuals affected with chronic pancreatitis (Audrezet 2002, Steiner 2011). This variant is reported in ClinVar (Variation ID: 53155), and is found in the African population with an allele frequency of 0.18% (46/24914 alleles) in the Genome Aggregation Database (v2.1.1). This variant occurs in the 3' untranslated region at a nucleotide that is moderately conserved, but the effect on the poly(a) signal is unknown. Due to limited information, the clinical significance of the c.*2G>A variant is uncertain at this time. References: Audrezet MP et al. Determination of the relative contribution of three genes-the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene-to the etiology of idiopathic chronic pancreatitis. Eur J Hum Genet. 2002 Feb;10(2):100-6. PMID: 11938439. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20. PMID: 21520337.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001002168	SCV001362319	likely benign	not specified	2022-05-16	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.*2G>A alters a non-conserved nucleotide located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.00014 in 251104 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.002 vs 0.013), allowing no conclusion about variant significance. c.*2G>A has been reported in the literature in individuals affected with idiopathic chronic pancreatitis, chronic obstructive pulmonary disease and CF-like symptoms (example, Solomon_2016, Steiner_2011, Mutesa_2009, Audrezet_2002). Furthermore, in one of these reports the authors conclude that the variant is "not reported to cause CF" (Solomon_2016). Therefore, these data do not allow any conclusion about variant significance. Co-occurrence with two other pathogenic variants in a specimen from a patient undergoing testing for CF has been observed in our laboratory (CFTR c.1521_1523delCTT, p.Phe508del; CFTR c.2290C>T, p.Arg764X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001409872	SCV001611906	likely benign	Cystic fibrosis	2023-09-08	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000176720	SCV001714852	uncertain significance	not provided	2020-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001409872	SCV002700673	likely benign	Cystic fibrosis	2023-02-19	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000176720	SCV004221650	uncertain significance	not provided	2023-11-21	criteria provided, single submitter	clinical testing	The CFTR c.*2G>A variant has been reported in the published literature in an individual with cystic fibrosis-like symptoms (PMID: 19017867 (2009)), in individuals with chronic pancreatitis (PMID: 11938439 (2002), 21520337 (2011)), and in an individual with chronic bronchitis (PMID: 27185048 (2016)). The frequency of this variant in the general population, 0.0018 (46/24914 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Johns Hopkins Genomics, Johns Hopkins University	RCV001409872	SCV004239029	uncertain significance	Cystic fibrosis	2023-12-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000176720	SCV005874594	uncertain significance	not provided	2024-08-30	criteria provided, single submitter	clinical testing	Nucleotide is not conserved across species and the substitution has no predicted effect on splicing; This variant is associated with the following publications: (PMID: 27185048, 21520337, 11938439, 19017867, 37313453)
PreventionGenetics, part of Exact Sciences	RCV004734602	SCV005361047	uncertain significance	CFTR-related disorder	2024-09-03	no assertion criteria provided	clinical testing	The CFTR c.*2G>A variant is located in the 3' untranslated region. This variant, also referred to as c.4443+2G>A or c.4575+2G>A, has been reported in the heterozygous state in two patients with chronic pancreatitis (Steiner et al., 2011. PubMed ID: 21520337, Supplement table 4; Audrezet et al., 2002. PubMed ID: 11938439, Table 1). However, no functional or family studies were performed in either report to confirm the pathogenicity of the c.*2G>A change. This variant is reported in 0.18% of alleles in individuals of African descent in gnomAD, which may be too common to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.