rs8065832

Variant names:

• chr17-17219013-G-A
• rs8065832
• NM_144997.7:c.1062+6C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-17219013-G-A
• chr17-17219013-G-C
• chr17-17219013-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001353229.2(FLCN):​c.1116+6C>T variant causes a splice 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_001353229.2 splice_region, intron
• Scores: Splicing: ADA: 0.00001352
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.476
• Publications: 35 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=-0.87).
• BP6: Variant 17-17219013-G-A is Benign according to our data. Variant chr17-17219013-G-A is described in ClinVar as Benign. ClinVar VariationId is 96468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353229.2. 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.1062+6C>T		splice_region intron	N/A	NP_659434.2
	FLCN	NM_001353229.2		c.1116+6C>T		splice_region intron	N/A	NP_001340158.1
	FLCN	NM_001353230.2		c.1062+6C>T		splice_region intron	N/A	NP_001340159.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.1062+6C>T		splice_region intron	N/A	ENSP00000285071.4
	ENSG00000264187	ENST00000427497.3	TSL:1	n.184+6C>T		splice_region intron	N/A	ENSP00000394249.3
	FLCN	ENST00000962729.1		c.1167+6C>T		splice_region intron	N/A	ENSP00000632788.1

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71703 AN: 151888 Hom.: 17675 Cov.: 31

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

GnomAD2 exomes AF: 0.506 AC: 126232 AN: 249690 AF XY: 0.497

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 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.: 47 AF XY: 0.488 AC XY: 354488 AN XY: 726344

African (AFR) AF: 0.354 AC: 11853 AN: 33444

American (AMR) AF: 0.551 AC: 24639 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 10865 AN: 26136

East Asian (EAS) AF: 0.647 AC: 25702 AN: 39696

South Asian (SAS) AF: 0.422 AC: 36356 AN: 86210

European-Finnish (FIN) AF: 0.644 AC: 34044 AN: 52876

Middle Eastern (MID) AF: 0.344 AC: 1833 AN: 5330

European-Non Finnish (NFE) AF: 0.488 AC: 542141 AN: 1111442

Other (OTH) AF: 0.475 AC: 28614 AN: 60288

GnomAD4 genome AF: 0.472 AC: 71725 AN: 152006 Hom.: 17681 Cov.: 31 AF XY: 0.478 AC XY: 35542 AN XY: 74308

African (AFR) AF: 0.365 AC: 15147 AN: 41450

American (AMR) AF: 0.492 AC: 7525 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1467 AN: 3470

East Asian (EAS) AF: 0.663 AC: 3417 AN: 5154

South Asian (SAS) AF: 0.434 AC: 2087 AN: 4812

European-Finnish (FIN) AF: 0.668 AC: 7054 AN: 10562

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.492 AC: 33412 AN: 67960

Other (OTH) AF: 0.430 AC: 907 AN: 2108

Alfa AF: 0.473 Hom.: 30582

Bravo AF: 0.457

Asia WGS AF: 0.568 AC: 1973 AN: 3478

EpiCase AF: 0.460

EpiControl AF: 0.463

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Birt-Hogg-Dube syndrome (5)
-	-	3	not provided (3)
-	-	2	Familial spontaneous pneumothorax (2)
-	-	1	Birt-Hogg-Dube syndrome 1 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.16
DANN	Benign	0.53
PhyloP100		-0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8065832; hg19: chr17-17122327; COSMIC: COSV53256751;