rs1736219

chr17-17224157-G-Achr17-17224157-G-Cchr17-17224157-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144997.7(FLCN):c.397-14C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,566,246 control chromosomes in the GnomAD database, including 181,520 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 15061 hom., cov: 33)

Exomes 𝑓: 0.48 ( 166459 hom. )

Consequence

FLCN
NM_144997.7 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.00600

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 17-17224157-G-A is Benign according to our data. Variant chr17-17224157-G-A is described in ClinVar as [Benign]. Clinvar id is 96486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17224157-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7 linkuse as main transcript	c.397-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9 linkuse as main transcript	c.397-14C>T	splice_polypyrimidine_tract_variant, intron_variant		1	NM_144997.7	P1	Q8NFG4-1
FLCN	ENST00000389169.9 linkuse as main transcript	c.397-14C>T	splice_polypyrimidine_tract_variant, intron_variant		1			Q8NFG4-2
FLCN	ENST00000417064.1 linkuse as main transcript	c.238-14C>T	splice_polypyrimidine_tract_variant, intron_variant		2
FLCN	ENST00000480316.1 linkuse as main transcript	n.349C>T	non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.407

AC:

61935

AN:

152008

Hom.:

15063

Cov.:

show subpopulations

Gnomad AFR

AF:

0.150

Gnomad AMI

AF:

0.681

Gnomad AMR

AF:

0.469

Gnomad ASJ

AF:

0.423

Gnomad EAS

AF:

0.663

Gnomad SAS

AF:

0.368

Gnomad FIN

AF:

0.668

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.490

Gnomad OTH

AF:

0.396

GnomAD3 exomes

AF:

0.482

AC:

84710

AN:

175706

Hom.:

21671

AF XY:

0.474

AC XY:

44425

AN XY:

93770

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.548

Gnomad ASJ exome

AF:

0.417

Gnomad EAS exome

AF:

0.658

Gnomad SAS exome

AF:

0.352

Gnomad FIN exome

AF:

0.661

Gnomad NFE exome

AF:

0.487

Gnomad OTH exome

AF:

0.457

GnomAD4 exome

AF:

0.478

AC:

676428

AN:

1414120

Hom.:

166459

Cov.:

AF XY:

0.475

AC XY:

332177

AN XY:

699100

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.530

Gnomad4 ASJ exome

AF:

0.415

Gnomad4 EAS exome

AF:

0.648

Gnomad4 SAS exome

AF:

0.353

Gnomad4 FIN exome

AF:

0.644

Gnomad4 NFE exome

AF:

0.486

Gnomad4 OTH exome

AF:

0.453

GnomAD4 genome

AF:

0.407

AC:

61943

AN:

152126

Hom.:

15061

Cov.:

AF XY:

0.415

AC XY:

30842

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.150

Gnomad4 AMR

AF:

0.469

Gnomad4 ASJ

AF:

0.423

Gnomad4 EAS

AF:

0.663

Gnomad4 SAS

AF:

0.368

Gnomad4 FIN

AF:

0.668

Gnomad4 NFE

AF:

0.490

Gnomad4 OTH

AF:

0.392

Alfa

AF:

0.461

Hom.:

17348

Bravo

AF:

0.385

Asia WGS

AF:

0.521

AC:

1809

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	397-14C>T in intron 5 of FLCN: This variant is not expected to have clinical sig nificance because it has been identified in 48.5% (4163/8588) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs1736219). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Birt-Hogg-Dube syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Familial spontaneous pneumothorax

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2016	Variant summary: The FLCN variant, c.397-14C>T is located at a non-conserved intronic position, not widely known to affect splicing, with 5/5 in silico programs via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest is observed in the large, broad control population, ExAC, with an allele frequency of 20124/41572 (1/2 including 4822 homozygotes), which significantly exceeds the estimated maximum expected allele frequency for a pathogenic FLCN variant of 1/769230. The variant of interest has also been reported by multiple reputable clinical laboratories as "benign." Therefore, the variant of interest has been classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

Cadd

Benign

0.71

Dann

Benign

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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