17-17222388-G-A

Variant names:

• chr17-17222388-G-A
• rs41356848
• NM_144997.7:c.779+113C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_144997.7(FLCN):​c.779+113C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,465,784 control chromosomes in the GnomAD database, including 382 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.016 (40 hom., cov: 32)
  • Exomes 𝑓: 0.020 (342 hom.)
• Consequence: FLCN NM_144997.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.137
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0163 (2475/152288) while in subpopulation AMR AF = 0.0286 (438/15290). AF 95% confidence interval is 0.0264. There are 40 homozygotes in GnomAd4. There are 1193 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2475 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	NM_144997.7	MANE Select	c.779+113C>T		intron	N/A	NP_659434.2
	FLCN	NM_001353229.2		c.833+113C>T		intron	N/A	NP_001340158.1
	FLCN	NM_001353230.2		c.779+113C>T		intron	N/A	NP_001340159.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.779+113C>T		intron	N/A	ENSP00000285071.4
	FLCN	ENST00000389169.9	TSL:1	c.779+113C>T		intron	N/A	ENSP00000373821.5
	ENSG00000264187	ENST00000427497.3	TSL:1	n.149-3334C>T		intron	N/A	ENSP00000394249.3

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2470 AN: 152170 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00497

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0210

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0204 AC: 26739 AN: 1313496 Hom.: 342 AF XY: 0.0199 AC XY: 13011 AN XY: 654298

African (AFR) AF: 0.00325 AC: 99 AN: 30438

American (AMR) AF: 0.0324 AC: 1206 AN: 37270

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 342 AN: 24644

East Asian (EAS) AF: 0.00 AC: 0 AN: 36226

South Asian (SAS) AF: 0.00794 AC: 624 AN: 78542

European-Finnish (FIN) AF: 0.0224 AC: 917 AN: 41028

Middle Eastern (MID) AF: 0.00287 AC: 15 AN: 5226

European-Non Finnish (NFE) AF: 0.0225 AC: 22596 AN: 1004376

Other (OTH) AF: 0.0169 AC: 940 AN: 55746

GnomAD4 genome AF: 0.0163 AC: 2475 AN: 152288 Hom.: 40 Cov.: 32 AF XY: 0.0160 AC XY: 1193 AN XY: 74448

African (AFR) AF: 0.00496 AC: 206 AN: 41568

American (AMR) AF: 0.0286 AC: 438 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4828

European-Finnish (FIN) AF: 0.0230 AC: 244 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0210 AC: 1427 AN: 68034

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.0175 Hom.: 8

Bravo AF: 0.0164

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.5
DANN	Benign	0.78
PhyloP100		0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs41356848; hg19: chr17-17125702;