17-17219013-G-A

Position:

chr17-17219013-G-A

Variant summary

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

The NM_144997.7(FLCN):c.1062+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,612,134 control chromosomes in the GnomAD database, including 195,880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 17681 hom., cov: 31)

Exomes 𝑓: 0.49 ( 178199 hom. )

Consequence

FLCN
NM_144997.7 splice_donor_region, intron

Scores

Splicing: ADA: 0.00001352

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.476

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=-0.87).

BP6

Variant 17-17219013-G-A is Benign according to our data. Variant chr17-17219013-G-A is described in ClinVar as [Benign]. Clinvar id is 96468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219013-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	Protein	UniProt
FLCN	NM_144997.7 linkuse as main transcript	c.1062+6C>T		splice_donor_region_variant, intron_variant		ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9 linkuse as main transcript	c.1062+6C>T		splice_donor_region_variant, intron_variant		1	NM_144997.7	ENSP00000285071	P1	Q8NFG4-1
FLCN	ENST00000577591.1 linkuse as main transcript	n.85+6C>T		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.472

AC:

71703

AN:

151888

Hom.:

17675

Cov.:

show subpopulations

Gnomad AFR

AF:

0.366

Gnomad AMI

AF:

0.682

Gnomad AMR

AF:

0.493

Gnomad ASJ

AF:

0.423

Gnomad EAS

AF:

0.663

Gnomad SAS

AF:

0.434

Gnomad FIN

AF:

0.668

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.492

Gnomad OTH

AF:

0.434

GnomAD3 exomes

AF:

0.506

AC:

126232

AN:

249690

Hom.:

32922

AF XY:

0.497

AC XY:

67230

AN XY:

135140

show subpopulations

Gnomad AFR exome

AF:

0.361

Gnomad AMR exome

AF:

0.564

Gnomad ASJ exome

AF:

0.417

Gnomad EAS exome

AF:

0.655

Gnomad SAS exome

AF:

0.422

Gnomad FIN exome

AF:

0.659

Gnomad NFE exome

AF:

0.488

Gnomad OTH exome

AF:

0.474

GnomAD4 exome

AF:

0.490

AC:

716047

AN:

1460128

Hom.:

178199

Cov.:

AF XY:

0.488

AC XY:

354488

AN XY:

726344

show subpopulations

Gnomad4 AFR exome

AF:

0.354

Gnomad4 AMR exome

AF:

0.551

Gnomad4 ASJ exome

AF:

0.416

Gnomad4 EAS exome

AF:

0.647

Gnomad4 SAS exome

AF:

0.422

Gnomad4 FIN exome

AF:

0.644

Gnomad4 NFE exome

AF:

0.488

Gnomad4 OTH exome

AF:

0.475

GnomAD4 genome

AF:

0.472

AC:

71725

AN:

152006

Hom.:

17681

Cov.:

AF XY:

0.478

AC XY:

35542

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.365

Gnomad4 AMR

AF:

0.492

Gnomad4 ASJ

AF:

0.423

Gnomad4 EAS

AF:

0.663

Gnomad4 SAS

AF:

0.434

Gnomad4 FIN

AF:

0.668

Gnomad4 NFE

AF:

0.492

Gnomad4 OTH

AF:

0.430

Alfa

AF:

0.476

Hom.:

24738

Bravo

AF:

0.457

Asia WGS

AF:

0.568

AC:

1973

AN:

3478

EpiCase

AF:

0.460

EpiControl

AF:

0.463

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2017	- -
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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2015	c.1062+6C>T in intron 9 of FLCN: This variant is not expected to have clinical s ignificance because it has been identified in 65% (4313/6562) of Finnish chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs8065832). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Birt-Hogg-Dube syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2016	Variant summary: c.1062+6C>T in FLCN gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 50.2% (60270/119978 chrs tested), including numerous homozygous occurrences. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.0003%, suggesting that it is a benign polymorphism. The variant of interest has been reported as Benign/Polymorphism by reputable database/clinical laboratory and published reports (Cho, 2008; Houweling, 2011). Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 14627671, 19733897) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial spontaneous pneumothorax

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.16

DANN

Benign

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.0

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