rs377731410
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000492.4(CFTR):c.1934T>A(p.Met645Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M645T) has been classified 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1934T>A | p.Met645Lys | missense_variant | 14/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1934T>A | p.Met645Lys | missense_variant | 14/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251134Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135788
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461796Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727190
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152316Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74478
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 01, 2020 | The p.M645K variant (also known as c.1934T>A), located in coding exon 14 of the CFTR gene, results from a T to A substitution at nucleotide position 1934. The methionine at codon 645 is replaced by lysine, an amino acid with similar properties. This alteration was reported in an individual with CFTR-related disorder; however, specific clinical information or the presence of a second alteration was not provided (Trujillano D et al. J Med Genet. 2013;50(7):455-62). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 645 of the CFTR protein (p.Met645Lys). This variant is present in population databases (rs377731410, gnomAD 0.008%). This missense change has been observed in individual(s) with CFTR-related disorder (PMID: 23687349). ClinVar contains an entry for this variant (Variation ID: 495905). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 24, 2022 | Variant summary: CFTR c.1934T>A (p.Met645Lys) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251134 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1934T>A has been reported in the literature as a non-informative heterozygous genotype (second allele not specified) in at-least one individual affected with CFTR-related disorder (example, Trujilano_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis Risk/CF/CFTR-related disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
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
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 14, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at