17-17219059-C-T
Variant summary
Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2
The NM_144997.7(FLCN):c.1022G>A(p.Arg341Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R341W) has been classified as Likely benign.
Frequency
Consequence
NM_144997.7 missense
Scores
Clinical Significance
Conservation
Publications
- Birt-Hogg-Dube syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
- Birt-Hogg-Dube syndrome 1Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
- familial spontaneous pneumothoraxInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
- renal carcinomaInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- colorectal cancerInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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FLCN | ENST00000285071.9 | c.1022G>A | p.Arg341Gln | missense_variant | Exon 9 of 14 | 1 | NM_144997.7 | ENSP00000285071.4 | ||
ENSG00000264187 | ENST00000427497.3 | n.149-5G>A | splice_region_variant, intron_variant | Intron 4 of 11 | 1 | ENSP00000394249.3 | ||||
FLCN | ENST00000577591.1 | n.45G>A | non_coding_transcript_exon_variant | Exon 1 of 2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152146Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.0000320 AC: 8AN: 250084 AF XY: 0.0000221 show subpopulations
GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461592Hom.: 0 Cov.: 35 AF XY: 0.0000468 AC XY: 34AN XY: 727096 show subpopulations
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152146Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74328 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
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In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (PMID: 35534704); This variant is associated with the following publications: (PMID: 30828692, 35534704) -
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Birt-Hogg-Dube syndrome 1 Uncertain:1Benign:1
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This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Colorectal cancer;C1868193:Familial spontaneous pneumothorax;CN074294:Nonpapillary renal cell carcinoma;CN375946:Birt-Hogg-Dube syndrome 1 Uncertain:1
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Birt-Hogg-Dube syndrome Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 341 of the FLCN protein (p.Arg341Gln). This variant is present in population databases (rs375352888, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 409387). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at