rs373504780

Variant names:

• chr17-17222492-G-A
• rs373504780
• NM_144997.7:c.779+9C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144997.7(FLCN):​c.779+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: FLCN NM_144997.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.512
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Birt-Hogg-Dube syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Birt-Hogg-Dube syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• familial spontaneous pneumothorax

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• renal carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264187 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-17222492-G-A is Benign according to our data. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222492-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 415611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000588 (86/1461832) while in subpopulation AMR AF = 0.00123 (55/44722). AF 95% confidence interval is 0.00097. There are 0 homozygotes in GnomAdExome4. There are 45 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.779+9C>T		intron_variant	Intron 7 of 13	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.779+9C>T		intron_variant	Intron 7 of 13	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.149-3438C>T		intron_variant	Intron 4 of 11	1		ENSP00000394249.3

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251294 AF XY: 0.000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000588 AC: 86 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45 AN XY: 727216

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00123 AC: 55 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111994

Other (OTH) AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74362

African (AFR) AF: 0.000121 AC: 5 AN: 41458

American (AMR) AF: 0.000327 AC: 5 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000125

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 29, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 06, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Birt-Hogg-Dube syndrome Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 06, 2023

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. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -

Birt-Hogg-Dube syndrome;C0346629:Colorectal cancer;C1868193:Familial spontaneous pneumothorax;C2931246:17p11.2 microduplication syndrome;CN074294:Nonpapillary renal cell carcinoma Benign:1

Jan 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FLCN-related disorder Benign:1

Dec 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.91
DANN	Benign	0.83
PhyloP100		0.51
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

Other links and lift over

dbSNP: rs373504780; hg19: chr17-17125806;