rs121909044
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000492.4(CFTR):c.1658G>A(p.Arg553Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000055 in 1,453,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R553G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1658G>A | p.Arg553Gln | missense_variant | 12/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1658G>A | p.Arg553Gln | missense_variant | 12/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000550 AC: 8AN: 1453920Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1AN XY: 723956
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 14, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 13, 1997 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 12, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 553 of the CFTR protein (p.Arg553Gln). This variant is present in population databases (rs121909044, gnomAD 0.3%). This missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 1284534, 1715308, 7545856, 19176844). ClinVar contains an entry for this variant (Variation ID: 7225). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at