7-117590357-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4BP6
The NM_000492.4(CFTR):c.1684G>A(p.Val562Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,602,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1684G>A | p.Val562Ile | missense_variant | Exon 13 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 152014Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000140 AC: 35AN: 250340Hom.: 0 AF XY: 0.000126 AC XY: 17AN XY: 135422
GnomAD4 exome AF: 0.000165 AC: 239AN: 1450402Hom.: 0 Cov.: 30 AF XY: 0.000166 AC XY: 120AN XY: 721284
GnomAD4 genome AF: 0.000197 AC: 30AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74384
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:4Benign:3
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. -
Variant NM_000492.4(CFTR):c.1684G>A (p.Val562Ile) is found frequent in Mendelics internal database. GnomAD frequency 0.0001679 with no Homozygotes. In Silico Predictors: Benign -
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 562 of the CFTR protein (p.Val562Ile). This variant is present in population databases (rs1800097, gnomAD 0.03%). This missense change has been observed in individual(s) with CFTR-related disorders including congenital absence of the vas deferens, oligospermia, chronic pancreatitis, and cystic fibrosis (PMID: 1379210, 9239681, 16189704, 17329263, 17331079, 19810821, 20021716, 20691141, 21520337, 23951356, 25667564, 25910067). This variant is also known as 1816G>A. ClinVar contains an entry for this variant (Variation ID: 35830). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CFTR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect CFTR function (PMID: 17098864, 21708286). 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. -
- -
- -
This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Cystic fibrosis, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:17098864). BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:17329263). -
- -
not provided Uncertain:2Benign:1
- -
- -
- -
CFTR-related disorder Uncertain:2
The CFTR c.1684G>A variant is predicted to result in the amino acid substitution p.Val562Ile. This variant was reported in a Moroccan patient with cystic fibrosis (Telleria et al. 1999. PubMed ID: 10447267). However, there was no further evidence that the p.Val562Ile variant was actually causative in this case. A later study reported cellular and genetic evidence that the p.Val562Ile variant may be benign (Roxo-Rosa et al. 2006. PubMed ID: 17098864). This variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD. In ClinVar, this variant has conflicting interpretations ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/35830/). While we suspect 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 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. -
Hereditary pancreatitis Uncertain:1
- -
not specified Benign:1
Variant summary: CFTR c.1684G>A (p.Val562Ile) results in a conservative amino acid change located in the ABC transporter-like domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. However, a recently developed integrative tool for in-silico analysis of missense variants in the CFTR gene (CYSMA), reporting a sensitivity of 89% and a specificity of 85% classified this variant as a True Negative (Sasorith_2020). This tool generates a set of computationally derived data, ranging from evolutionary conservation to functional observations from threedimensional structures, provides all available allelic frequencies, clinical observations, and references for functional studies. The variant allele was found at a frequency of 0.00014 in 250586 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00014 vs 0.013), allowing no conclusion about variant significance. c.1684G>A, has been reported in the literature in individuals affected with a wide spectrum of phenotypes ranging from asymptomatic to CF, CBAVD, infertility, diffuse bronchiectasis and idiopathic chronic pancreatitis, many of whom were not uniformly analyzed and had non-informative genotypes (Braekeleer_1996, Peuchal_1999, Telleria_1999, Grangeia_2004, Cohn_2005, Claustres_2017, Lucarelli_2017). These data do not allow any conclusion about variant significance. In addition, several publications have reported this variant in cis as c.[1210-34_1210-6TG[11]T[5];1684G>A] (TG11T5, T5, A1006E) in combination with another pathogenic variant in trans that could have explained some of the symptoms reported (McGinniss_2005, Alonso_2007, Ratbi_2007, Lucarelli_2015, Sofia_2018). Of note, at-least one patient homozygous for 2347delG with this variant in cis on both his alleles has been reported in an unpublished study (Giordan et al) (cited by Ratbi_2007). Similarly, at-least 2 unaffected patients with this variant and p.F508del in trans have been reported as a personal communication with C. Barreto (cited by Roxo-Rosa_2006). Recently, this variant genotype (c.[1210-34_1210-6TG[11]T[5];1684G>A]) was reported with a hemizygous causative highly penetrant truncation variant in the X-linked ADGRG2 gene (c.251C>G, p.Ser84*) in a patient with CBAVD, bilateral epididymis enlargement, azoospermia and hypovolemia (Pagin_2020). The authors concluded that the presence of the CFTR variant in this patient may be incidental and that the loss of function variant in ADGRG2 is sufficient to produce the CAVD phenotype. These reports provide additional supporting evidence that the variant of interest was not causative of disease in these patients. Three independent functional studies report no effects on either of CFTR trafficking, the maturation process, channel activity or mRNA expression levels (Roxo-Rosa_2006, Fresquet_2011, Raraigh_2018). The CFTR2 database reports this variant as not causative of CF when combined with another CF-causing variant. The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 9239681, 10923036, 28603918, 15758663, 1379210, 21708286, 18716917, 15333598, 17572159, 28736296, 25910067, 16189704, 31845523, 20651897, 10445602, 29805046, 17329263, 17098864, 31674704, 30134826, 10447267, 20691141, 19812525). ClinVar contains an entry for this variant (Variation ID: 35830). Based on the evidence outlined above, the variant was classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at