rs398124526
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_144997.7(FLCN):c.1203_1204insC(p.Ile402HisfsTer54) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R401R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_144997.7 frameshift
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 | UniProt |
---|---|---|---|---|---|---|---|
FLCN | NM_144997.7 | c.1203_1204insC | p.Ile402HisfsTer54 | frameshift_variant | 11/14 | ENST00000285071.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.1203_1204insC | p.Ile402HisfsTer54 | frameshift_variant | 11/14 | 1 | NM_144997.7 | P1 | |
MPRIP | ENST00000578209.5 | c.*18-1013dup | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249388Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135170
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461602Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727104
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 14, 2015 | The c.1203dupC variant in the FLCN gene causes a frameshift starting with codon Isoleucine 402, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 54 of the new reading frame, denoted p.Ile402HisfsX54. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. - |
Pathogenic, no assertion criteria provided | clinical testing | Eurofins Ntd Llc (ga) | Feb 28, 2013 | - - |
Birt-Hogg-Dube syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 15, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 20, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 96473). This variant has not been reported in the literature in individuals affected with FLCN-related conditions. This variant is present in population databases (rs398124526, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ile402Hisfs*54) 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). - |
Familial spontaneous pneumothorax Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 07, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 12, 2024 | The c.1203dupC pathogenic mutation, located in coding exon 8 of the FLCN gene, results from a duplication of C at nucleotide position 1203, causing a translational frameshift with a predicted alternate stop codon (p.I402Hfs*54). 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