Variant 17-17224093-GC-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The ENST00000285071.9(FLCN):c.446delG(p.Gly149fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G149G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FLCN
ENST00000285071.9 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.37

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]

FLCN links:

ENSG00000264187 (HGNC:):

ENSG00000264187 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 17-17224093-GC-G is Pathogenic according to our data. Variant chr17-17224093-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179123.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7 linkuse as main transcript	c.446delG	p.Gly149fs	frameshift_variant	6/14	ENST00000285071.9	NP_659434.2	Q8NFG4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9 linkuse as main transcript	c.446delG	p.Gly149fs	frameshift_variant	6/14	1	NM_144997.7	ENSP00000285071.4		Q8NFG4-1
ENSG00000264187	ENST00000427497.3 linkuse as main transcript	n.148+3896delG		intron_variant		1		ENSP00000394249.3		J3QW42

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459610

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725820

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Birt-Hogg-Dube syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 29, 2016

The p.Gly149fs variant in FLCN has been identified by our laboratory in 1 indivi dual with Birt-Hogg-Dube syndrome. It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amin o acid sequence beginning at position 149 and leads to a premature termination c odon 28 amino acids downstream. This alteration is then predicted to lead to a t runcated or absent protein. Frameshift and other truncating variants in FLCN ha ve been associated with Birt-Hogg-Dube syndrome and recurrent spontaneous pneumo thoraces (Nickerson 2002). In summary, although additional studies are required to fully establish its clinical significance, the p.Gly149fs variant is likely p athogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over