chr7-117587802-G-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.1648G>T(p.Gly550Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
CFTR
NM_000492.4 stop_gained
NM_000492.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 8.82
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-117587802-G-T is Pathogenic according to our data. Variant chr7-117587802-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 53312.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117587802-G-T is described in Lovd as [Pathogenic]. Variant chr7-117587802-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1648G>T | p.Gly550Ter | stop_gained | 12/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1648G>T | p.Gly550Ter | stop_gained | 12/27 | 1 | NM_000492.4 | ENSP00000003084 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:4
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 19, 2019 | The p.G550* pathogenic mutation (also known as c.1648G>T), located in coding exon 12 of the CFTR gene, results from a G to T substitution at nucleotide position 1648. This changes the amino acid from a glycine to a stop codon within coding exon 12. 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 29, 2022 | Variant summary: CFTR c.1648G>T (p.Gly550X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250898 control chromosomes. c.1648G>T has been reported in the literature in individuals affected with Cystic Fibrosis (example, Estivill_1997, McCague_2019). One clinical diagnostic laboratory and the CFTR2 database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 29, 2020 | This variant has been observed in individual(s) with CFTR-related conditions (PMID: 23974870). ClinVar contains an entry for this variant (Variation ID: 53312). This sequence change creates a premature translational stop signal (p.Gly550*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). 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. - |
CFTR-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
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