7-117590439-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000492.4(CFTR):c.1766G>C(p.Ser589Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000276 in 1,448,114 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 Uncertain significance (★).
Frequency
Consequence
NM_000492.4 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1766G>C | p.Ser589Thr | missense_variant, splice_region_variant | Exon 13 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000276 AC: 4AN: 1448114Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1AN XY: 720218
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: CFTR c.1766G>C (p.Ser589Thr) results in a conservative amino acid change located in the first ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This variant falls onto the last nucleotide of exon 13, therefore can also affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249234 control chromosomes (gnomAD v2.1 exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1766G>C has been reported in the literature in a compound heterozygous individuals affected with Cystic Fibrosis, who carried a pathogenic 2nd variant (Kinnunen_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant affecting the same nucleotide (CFTR c.1766G>A (p.Ser589Asn)) is classified as pathogenic by our lab. The following publication have been ascertained in the context of this evaluation (PMID: 16051530). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Cystic fibrosis Other:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at