rs1554391489

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000492.4(CFTR):​c.2982_2988+2delCATCCAGGT​(p.Ile995fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,860 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: 32)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CFTR
NM_000492.4 frameshift, splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.25
Variant links:
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]

Genome browser will be placed here

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 7-117606745-TTCATCCAGG-T is Pathogenic according to our data. Variant chr7-117606745-TTCATCCAGG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CFTRNM_000492.4 linkuse as main transcriptc.2982_2988+2delCATCCAGGT p.Ile995fs frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant 18/27 ENST00000003084.11 NP_000483.3 P13569-1A0A024R730

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkuse as main transcriptc.2982_2988+2delCATCCAGGT p.Ile995fs frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant 18/271 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.14e-7
AC:
1
AN:
1399860
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
700394
show subpopulations
Gnomad4 AFR exome
AF:
0.0000312
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 07, 2023Variant summary: CFTR c.2982_2988+2delCATCCAGGT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251096 control chromosomes. c.2982_2988+2delCATCCAGGT has been reported in the literature in individuals affected with Cystic Fibrosis (Schrijver_2016). 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: 26708955). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 02, 2024This variant results in the deletion of part of exon 18 (c.2982_2988+2del) of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cystic fibrosis (PMID: 26708955). ClinVar contains an entry for this variant (Variation ID: 439070). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 06, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554391489; hg19: chr7-117246799; API