7-117603644-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000492.4(CFTR):c.2770G>A(p.Asp924Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D924H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.2770G>A | p.Asp924Asn | missense_variant | 17/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.2770G>A | p.Asp924Asn | missense_variant | 17/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152164Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251412Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135872
GnomAD4 exome AF: 0.000140 AC: 204AN: 1461752Hom.: 0 Cov.: 32 AF XY: 0.000143 AC XY: 104AN XY: 727184
GnomAD4 genome AF: 0.000151 AC: 23AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10AN XY: 74326
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Uncertain:4Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2023 | The p.D924N variant (also known as c.2770G>A), located in coding exon 17 of the CFTR gene, results from a G to A substitution at nucleotide position 2770. The aspartic acid at codon 924 is replaced by asparagine, an amino acid with highly similar properties. This variant was detected in two individuals with cystic fibrosis; however, additional genotype and phenotype information was not provided (Alonso MJ et al. Ann. Hum. Genet., 2007 Mar;71:194-201; Zitkiewicz E et al. PLoS ONE, 2014 Feb;9:e89094). In one French individual, the p.D924N variant was reported in cis with p.F508del (Baatallah N et al. Hum. Mutat., 2018 Apr;39:506-514). This variant was also identified in trans a 5T variant in an individual with recurrent pancreatitis (Koyano S et al. Pancreas, 2010 Jul;39:686-7). This amino acid position is conserved through reptiles. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
Likely pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3_STR, PM2_SUP, PM5_SUP, PP3, PS3_SUP, PP4 - |
Uncertain significance, reviewed by expert panel | research | CFTR2 | Dec 20, 2019 | - - |
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 27, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 924 of the CFTR protein (p.Asp924Asn). This variant is present in population databases (rs201759207, gnomAD 0.01%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 20562583). ClinVar contains an entry for this variant (Variation ID: 53565). 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 with a positive predictive value of 80%. 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. - |
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 19, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 22, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 05, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 27, 2017 | The CFTR c.2770G>A; p.Asp924Asn variant (rs201759207) has been reported in cystic fibrosis patients, but its clinical significance was not determined (Alonso 2006, Zietkiewicz 2014). It is listed in ClinVar (Variation ID: 53565) and observed in the general population at an overall frequency of 0.009% (25/277152 alleles) in the Genome Aggregation Database. The aspartic acid at codon 924 is highly conserved, but computational algorithms (PolyPhen-2: probably damaging; SIFT: tolerated) are inconclusive on the variant's impact on the protein. Due to the limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Alonso M et al. Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Ann Hum Genet. 2007; 71(Pt 2):194-201. Zietkiewicz E et al. CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients. PLoS One. 2014; 9(2):e89094. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2023 | Variant summary: CFTR c.2770G>A (p.Asp924Asn) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. In a minigene assay this variant has been shown to cause exon skipping (Baatallah_2018), however, the exact in-vivo consequences of this finding are not known. The authors speculated that this variant when present in cis with p.Phe508del could result in a reduced amount of full length CFTR, hence reducing the amount of CFTR-p.Phe508del targeted by corrector/potentiator treatment. The variant allele was found at a frequency of 6.8e-05 in 251412 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (6.8e-05 vs 0.013), allowing no conclusion about variant significance. c.2770G>A has been reported in the literature in individuals affected with Cystic Fibrosis (CF), CF- related disorders as well as pancreatic cancer (e.g. Alonso_2007, deCid_2010, Koyano_2010, Zietkiewicz_2013, Guan_2018, Tamura_2019, Claustres_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. CFTR2 database also report this variant as variant of uncertain significance. Co-occurrences with other pathogenic variant(s) have been reported (Baatallah_2018, CFTR c.1521_1523del, p.F508del), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 29271547, 31883651, 28603918, 29997923, 20562583, 25735457, 29669919, 24586523, 19812525). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance (n=10) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
CFTR-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 23, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at