rs41525346

Variant names:

• chr17-17226117-A-G
• rs41525346
• NM_144997.7:c.396+59T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_144997.7(FLCN):​c.396+59T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0779 in 1,605,736 control chromosomes in the GnomAD database, including 5,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (381 hom., cov: 32)
  • Exomes 𝑓: 0.080 (4991 hom.)
• Consequence: FLCN NM_144997.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.970
• Publications: 11 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, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, Ambry Genetics, Genomics England PanelApp
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.023).
• BP6: Variant 17-17226117-A-G is Benign according to our data. Variant chr17-17226117-A-G is described in ClinVar as Benign. ClinVar VariationId is 41858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0913 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144997.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	NM_144997.7	MANE Select	c.396+59T>C		intron	N/A	NP_659434.2
	FLCN	NM_001353229.2		c.396+59T>C		intron	N/A	NP_001340158.1
	FLCN	NM_001353230.2		c.396+59T>C		intron	N/A	NP_001340159.1	Q8NFG4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.396+59T>C		intron	N/A	ENSP00000285071.4	Q8NFG4-1
	FLCN	ENST00000389169.9	TSL:1	c.396+59T>C		intron	N/A	ENSP00000373821.5	Q8NFG4-2
	ENSG00000264187	ENST00000427497.3	TSL:1	n.148+1873T>C		intron	N/A	ENSP00000394249.3	J3QW42

Frequencies

GnomAD3 genomes AF: 0.0629 AC: 9564 AN: 152062 Hom.: 380 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0955

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0854

Gnomad FIN AF: 0.0631

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0839

Gnomad OTH AF: 0.0842

GnomAD2 exomes AF: 0.0768 AC: 18722 AN: 243898 AF XY: 0.0796

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.0620

Gnomad NFE exome AF: 0.0822

Gnomad OTH exome AF: 0.0901

GnomAD4 exome AF: 0.0795 AC: 115595 AN: 1453556 Hom.: 4991 Cov.: 31 AF XY: 0.0806 AC XY: 58295 AN XY: 722984

African (AFR) AF: 0.0124 AC: 414 AN: 33336

American (AMR) AF: 0.108 AC: 4705 AN: 43624

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3076 AN: 25820

East Asian (EAS) AF: 0.000204 AC: 8 AN: 39148

South Asian (SAS) AF: 0.0998 AC: 8505 AN: 85202

European-Finnish (FIN) AF: 0.0645 AC: 3428 AN: 53180

Middle Eastern (MID) AF: 0.104 AC: 599 AN: 5748

European-Non Finnish (NFE) AF: 0.0814 AC: 90136 AN: 1107460

Other (OTH) AF: 0.0787 AC: 4724 AN: 60038

GnomAD4 genome AF: 0.0628 AC: 9560 AN: 152180 Hom.: 381 Cov.: 32 AF XY: 0.0635 AC XY: 4721 AN XY: 74400

African (AFR) AF: 0.0150 AC: 623 AN: 41534

American (AMR) AF: 0.0954 AC: 1459 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 441 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5172

South Asian (SAS) AF: 0.0857 AC: 413 AN: 4818

European-Finnish (FIN) AF: 0.0631 AC: 669 AN: 10602

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0839 AC: 5704 AN: 67974

Other (OTH) AF: 0.0833 AC: 176 AN: 2112

Alfa AF: 0.0754 Hom.: 196

Bravo AF: 0.0619

Asia WGS AF: 0.0340 AC: 120 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Birt-Hogg-Dube syndrome (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.9
DANN	Benign	0.92
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs41525346; hg19: chr17-17129431; COSMIC: COSV53258660; COSMIC: COSV53258660;