rs397508211
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.1466C>A(p.Ser489Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,611,132 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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S489S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000492.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1466C>A | p.Ser489Ter | stop_gained | 11/27 | ENST00000003084.11 | |
CFTR-AS1 | NR_149084.1 | n.221+1196G>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1466C>A | p.Ser489Ter | stop_gained | 11/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251332Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135840
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1459060Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14AN XY: 726026
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74294
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:7
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 12, 2023 | Variant summary: CFTR c.1466C>A (p.Ser489X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251332 control chromosomes. c.1466C>A has been reported in the literature in a homozygous individual and multiple compound heterozygous individuals affected with Cystic Fibrosis (Example: DeBie_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22627569). Seven 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 23, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2022 | This sequence change creates a premature translational stop signal (p.Ser489*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 53259). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 21520337, 22627569, 23974870). This variant is present in population databases (rs397508211, gnomAD 0.002%). - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 13, 2022 | The p.S489* pathogenic mutation (also known as c.1466C>A), located in coding exon 11 of the CFTR gene, results from a C to A substitution at nucleotide position 1466. This changes the amino acid from a serine to a stop codon within coding exon 11. In one study, this mutation was described as compound heterozygous in 12 individuals with another pathogenic mutation and as homozygous in one individual all with classic cystic fibrosis (De Bie I et al. Genet Med. 2012;14(10):883-886). This mutation has also been observed in an individual with congenital bilateral absence of the vas deferens (Steiner B et al. Hum Mutat. 2011;32(8):912-20). Affected individuals carrying this pathogenic mutation had elevated sweat chloride levels, pancreatic insufficiency, and higher rates of Pseduomonas infection (Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167 and The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed June 13, 2022). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
CFTR-related disorder Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 23, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 08, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at