NM_000492.4:c.1950C>A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000492.4(CFTR):c.1950C>A(p.Phe650Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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CFTR | NM_000492.4 | c.1950C>A | p.Phe650Leu | missense_variant | Exon 14 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152092Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251026Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135760
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461758Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727180
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74414
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:5
The c.1950C>A (p.F650L) alteration is located in exon 14 (coding exon 14) of the CFTR gene. This alteration results from a C to A substitution at nucleotide position 1950, causing the phenylalanine (F) at amino acid position 650 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
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This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 650 of the CFTR protein (p.Phe650Leu). This variant is present in population databases (rs200204024, gnomAD 0.04%). This missense change has been observed in individual(s) with bronchiectasis (PMID: 17035430). ClinVar contains an entry for this variant (Variation ID: 550836). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. 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. -
not specified Uncertain:1
Variant summary: CFTR c.1950C>A (p.Phe650Leu) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251026 control chromosomes, predominantly at a frequency of 0.00044 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1950C>A has been reported in the literature in one individual with bronchiectasis who had normal sweat chloride levels (Ziedalski_2006). It has also been reported in individuals with unrelated/unspecified phenotypes (e.g. Qiu_2017, Ni_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17035430, 28027573, 35313924). ClinVar contains an entry for this variant (Variation ID: 550836). Based on the evidence outlined above, the variant was classified as uncertain significance. -
CFTR-related disorder Uncertain:1
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Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at