rs397508232
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2
The NM_000492.4(CFTR):c.1584+53_1584+63dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00068 in 1,251,778 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0032 ( 5 hom., cov: 32)
Exomes 𝑓: 0.00034 ( 1 hom. )
Consequence
CFTR
NM_000492.4 intron
NM_000492.4 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.959
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 Benign. Variant got -12 ACMG points.
BP6
?
Variant 7-117559705-C-CTACCCAAATTA is Benign according to our data. Variant chr7-117559705-C-CTACCCAAATTA is described in ClinVar as [Likely_benign]. Clinvar id is 439056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
?
High Homozygotes in GnomAd4 at 5 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1584+53_1584+63dup | intron_variant | ENST00000003084.11 | |||
CFTR-AS1 | NR_149084.1 | n.221+1027_221+1028insTAATTTGGGTA | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1584+53_1584+63dup | intron_variant | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00315 AC: 479AN: 152122Hom.: 5 Cov.: 32
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GnomAD3 exomes AF: 0.000662 AC: 154AN: 232686Hom.: 0 AF XY: 0.000531 AC XY: 67AN XY: 126264
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GnomAD4 exome AF: 0.000337 AC: 370AN: 1099538Hom.: 1 Cov.: 14 AF XY: 0.000295 AC XY: 166AN XY: 563352
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GnomAD4 genome ? AF: 0.00316 AC: 481AN: 152240Hom.: 5 Cov.: 32 AF XY: 0.00296 AC XY: 220AN XY: 74450
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 25, 2018 | Variant summary: CFTR c.1584+53_1584+63dup11 is located at a deep intronic position not widely known to affect splicing. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00088 in 259470 control chromosomes, predominantly within the African subpopulation in the gnomAD database at a frequency of 0.0086, including 1 homozygote. The observed variant frequency within African control individuals is approximately 1.5-fold above the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk phenotype (0.0063), suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.1584+53_1584+63dup11 has been reported in the literature without evidence for pathogenicity, thus these reports do not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis Risk. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. - |
Cystic fibrosis Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Apr 14, 2023 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 28, 2022 | - - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at