rs1555609896
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_144997.7(FLCN):c.652C>T(p.Arg218Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,884 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. R218H) has been classified as Uncertain significance.
Frequency
Consequence
NM_144997.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLCN | NM_144997.7 | c.652C>T | p.Arg218Cys | missense_variant | 7/14 | ENST00000285071.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.652C>T | p.Arg218Cys | missense_variant | 7/14 | 1 | NM_144997.7 | P1 | |
FLCN | ENST00000389169.9 | c.652C>T | p.Arg218Cys | missense_variant | 7/8 | 1 | |||
FLCN | ENST00000466317.1 | n.495C>T | non_coding_transcript_exon_variant | 1/2 | 2 | ||||
FLCN | ENST00000480316.1 | n.618C>T | non_coding_transcript_exon_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727244
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 14, 2021 | The p.R218C variant (also known as c.652C>T), located in coding exon 4 of the FLCN gene, results from a C to T substitution at nucleotide position 652. The arginine at codon 218 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly 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 alteration remains unclear. - |
Birt-Hogg-Dube syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 218 of the FLCN protein (p.Arg218Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLCN-related conditions. ClinVar contains an entry for this variant (Variation ID: 460626). 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 FLCN protein function with a negative 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at