rs397508204
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.1409_1418delTGATTATGGG(p.Val470GlufsTer54) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
CFTR
NM_000492.4 frameshift
NM_000492.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.43
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 7-117559477-TGGTGATTATG-T is Pathogenic according to our data. Variant chr7-117559477-TGGTGATTATG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.1409_1418delTGATTATGGG | p.Val470GlufsTer54 | frameshift_variant | Exon 11 of 27 | ENST00000003084.11 | NP_000483.3 | |
| CFTR-AS1 | NR_149084.1 | n.221+1246_221+1255delCATAATCACC | intron_variant | Intron 2 of 2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.89e-7 AC: 1AN: 1451958Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 723134
GnomAD4 exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:2Other:1
-
ClinVar Staff, National Center for Biotechnology Information (NCBI)
Significance: not provided
Review Status: no classification provided
Collection Method: literature only
- -
Jun 05, 2018
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Nov 05, 2018
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at