rs1736219

Variant names:

• chr17-17224157-G-A
• rs1736219
• NM_144997.7:c.397-14C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-17224157-G-A
• chr17-17224157-G-C
• chr17-17224157-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144997.7(FLCN):​c.397-14C>T variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.00600

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]

ENSG00000264187 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.397-14C>T		intron_variant	Intron 5 of 13	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.397-14C>T		intron_variant	Intron 5 of 13	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.148+3833C>T		intron_variant	Intron 4 of 11	1		ENSP00000394249.3

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61935 AN: 152008 Hom.: 15063 Cov.: 33

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

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.: 33 AF XY: 0.475 AC XY: 332177 AN XY: 699100

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.: 33 AF XY: 0.415 AC XY: 30842 AN XY: 74366

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:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Apr 10, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Birt-Hogg-Dube syndrome Benign:4

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

May 04, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial spontaneous pneumothorax Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Birt-Hogg-Dube syndrome 1 Benign:1

Oct 22, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

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

Other links and lift over

dbSNP: rs1736219; hg19: chr17-17127471; COSMIC: COSV53256759; COSMIC: COSV53256759;