7-117592643-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000492.4(CFTR):c.2476G>A(p.Glu826Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,389,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
CFTR
NM_000492.4 missense
NM_000492.4 missense
Scores
10
6
3
Clinical Significance
Conservation
PhyloP100: 9.04
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.946
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.2476G>A | p.Glu826Lys | missense_variant | 14/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.2476G>A | p.Glu826Lys | missense_variant | 14/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000260 AC: 5AN: 192496Hom.: 0 AF XY: 0.0000291 AC XY: 3AN XY: 103138
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GnomAD4 exome AF: 0.0000130 AC: 18AN: 1389730Hom.: 0 Cov.: 31 AF XY: 0.0000146 AC XY: 10AN XY: 686762
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cystic fibrosis Uncertain:4Other:1
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 09, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 826 of the CFTR protein (p.Glu826Lys). This variant is present in population databases (rs397508381, gnomAD 0.004%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 27728908, 28603918). ClinVar contains an entry for this variant (Variation ID: 53495). 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 expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 9736778, 9849891). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2023 | The p.E826K variant (also known as c.2476G>A), located in coding exon 14 of the CFTR gene, results from a G to A substitution at nucleotide position 2476. The glutamic acid at codon 826 is replaced by lysine, an amino acid with similar properties. This alteration was detected in heterozygous state in an individual with sarcoidosis, who did not have a second CFTR variant identified (Bombieri C et al. Hum. Genet., 1998 Dec;103:718-22). In vitro studies did not find significant difference between the mutant and wild type (Wei L et al. FEBS Lett., 1998 Nov;439:121-6; Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 27, 2023 | Variant summary: CFTR c.2476G>A (p.Glu826Lys) results in a conservative amino acid change located in the CFTR regulator domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 192496 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2476G>A has been reported in the literature in control individuals (Morea 2005, Tzetis 2007), in a CF patient (Prontera 2016), and in a sarcoidosis patient (Bombieri 1998). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. At-least one co-occurrence in cis with other pathogenic variant(s) have been reported (CFTR c.5T_TG12; CFTR c.3308T>A, p.I1103K), providing supporting evidence for a benign role (Claustres 2017, CFTR-France database, Prontera_2016). At least two publications report experimental evidence evaluating an impact on protein function. While the variant did not affect the protein maturation, it was reported to result in a slightly lower open channel probability, however single channel conductances were not different from the wild-type (Wei 1998, Vankeerberghen 1998). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 23, 2019 | - - |
CFTR-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 20, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;.
Sift4G
Uncertain
D;.;D;.
Polyphen
D;.;.;.
Vest4
MutPred
Gain of ubiquitination at E826 (P = 0.0094);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at