rs398124525
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000285071.9(FLCN):βc.1179delβ(p.Met394CysfsTer74) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,548 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. T393T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000285071.9 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLCN | NM_144997.7 | c.1179del | p.Met394CysfsTer74 | frameshift_variant, splice_region_variant | 11/14 | ENST00000285071.9 | NP_659434.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.1179del | p.Met394CysfsTer74 | frameshift_variant, splice_region_variant | 11/14 | 1 | NM_144997.7 | ENSP00000285071 | P1 | |
MPRIP | ENST00000578209.5 | c.*18-988del | intron_variant | 3 | ENSP00000464276 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461548Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727080
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 30, 2023 | PM2_moderate, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 17, 2015 | The c.1179delC pathogenic variant in the FLCN gene causes a frameshift starting with codon Methionine 394, changes this amino acid to a Cysteine residue and creates a premature Stop codon at position 74 of the new reading frame, denoted p.Met394CysfsX74. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 19, 2013 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2022 | The c.1179delC pathogenic mutation, located in coding exon 8 of the FLCN gene, results from a deletion of one nucleotide at nucleotide position 1179, causing a translational frameshift with a predicted alternate stop codon (p.M394Cfs*74). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with FLCN-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
Birt-Hogg-Dube syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 24, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 96471). This variant has not been reported in the literature in individuals affected with FLCN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met394Cysfs*74) 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at