rs146795445
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000492.4(CFTR):c.3873+2T>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000492.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3873+2T>C | splice_donor_variant | ENST00000003084.11 | NP_000483.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3873+2T>C | splice_donor_variant | 1 | NM_000492.4 | ENSP00000003084 | P2 | |||
ENST00000456270.1 | n.65+4756A>G | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250620Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135458
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460958Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726758
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 09, 2016 | Variant summary: The CFTR c.3873+2T>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the loss of a canonical splice donor site. This variant was found in 1/118992 control chromosomes at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in numerous affected individuals in the literature, both pancreatic sufficient and insufficient patients. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 14, 2017 | - - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 06, 2022 | The c.3873+2T>C intronic pathogenic mutation (also known as 4005+2T>C) results from a T to C substitution two nucleotides after coding exon 23 in the CFTR gene. This mutation was identified in a Norwegian infant with elevated sweat chloride levels in conjunction with p.F508del; however, the phase was not confirmed (Lundman E et al. J. Cyst. Fibros., 2016 May;15:318-24). This alteration is one of the most commonly reported mutations in Norwegian individuals with cystic fibrosis, accounting for 3.8% of alleles in that population (Munthe-Kaas MC et al. Respir Med, 2006 Dec;100:2121-8). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 07, 2023 | Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 19318346, 26348465). This variant is present in population databases (rs146795445, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 23 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). ClinVar contains an entry for this variant (Variation ID: 53828). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. - |
Likely pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_STR, PM2_SUP, PM3_STR - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 27, 2020 | PVS1, PM2, PP3, PP4, PP5 - |
CFTR-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at