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

Genomes: not found (cov: 32)

Consequence

FLCN
NM_144997.7 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.69
Variant links:
Genes affected
FLCN (HGNC:27310): (folliculin) This gene is located within the Smith-Magenis syndrome region on chromosome 17. Mutations in this gene are associated with Birt-Hogg-Dube syndrome, which is characterized by fibrofolliculomas, renal tumors, lung cysts, and pneumothorax. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-17216465-G-C is Pathogenic according to our data. Variant chr17-17216465-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17216465-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLCNNM_144997.7 linkc.1215C>G p.Tyr405* stop_gained Exon 11 of 14 ENST00000285071.9 NP_659434.2 Q8NFG4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLCNENST00000285071.9 linkc.1215C>G p.Tyr405* stop_gained Exon 11 of 14 1 NM_144997.7 ENSP00000285071.4 Q8NFG4-1
ENSG00000264187ENST00000427497.3 linkn.*49C>G non_coding_transcript_exon_variant Exon 7 of 12 1 ENSP00000394249.3 J3QW42
ENSG00000264187ENST00000427497.3 linkn.*49C>G 3_prime_UTR_variant Exon 7 of 12 1 ENSP00000394249.3 J3QW42
MPRIPENST00000578209.5 linkc.*18-1025G>C intron_variant Intron 5 of 5 3 ENSP00000464276.1 J3QRL2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Dec 27, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Feb 09, 2024
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Birt-Hogg-Dube syndrome Pathogenic:2
Aug 03, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

Sep 21, 2023
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Nov 09, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.92
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs786202541; hg19: chr17-17119779; API