17-17216465-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_144997.7(FLCN):c.1215C>G(p.Tyr405*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_144997.7 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.1215C>G | p.Tyr405* | stop_gained | Exon 11 of 14 | 1 | NM_144997.7 | ENSP00000285071.4 | ||
ENSG00000264187 | ENST00000427497.3 | n.*49C>G | non_coding_transcript_exon_variant | Exon 7 of 12 | 1 | ENSP00000394249.3 | ||||
ENSG00000264187 | ENST00000427497.3 | n.*49C>G | 3_prime_UTR_variant | Exon 7 of 12 | 1 | ENSP00000394249.3 | ||||
MPRIP | ENST00000578209.5 | c.*18-1025G>C | intron_variant | Intron 5 of 5 | 3 | ENSP00000464276.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Nonsense variant predicted to result in protein truncation [or nonsense mediated decay] in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.1670C>G; This variant is associated with the following publications: (PMID: 25525159, 15852235, 28151982, 29357828, 18234728) -
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Birt-Hogg-Dube syndrome Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 185892). This premature translational stop signal has been observed in individual(s) with clinical diagnosis or suspicion of Birt-Hogg-Dubé syndrome (PMID: 18234728, 28151982). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr405*) in the FLCN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). -
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.Y405* pathogenic mutation (also known as c.1215C>G), located in coding exon 8 of the FLCN gene, results from a C to G substitution at nucleotide position 1215. This changes the amino acid from a tyrosine to a stop codon within coding exon 8. This alteration has been described in individuals with clinical features of Birt-Hogg-Dubé syndrome (Toro JR et al. J. Med. Genet. 2008 Jun;45:321-31; Park HJ et al. PLoS ONE 2017 Feb;12:e0170713; Ambry internal data). Of note, this alteration is also designated as c.1670C>G in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at