rs41400246

Variant names:

• chr17-17221311-C-T
• rs41400246
• ENST00000389169.9:c.*68G>A

Variant summary

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

The ENST00000389169.9(FLCN):​c.*68G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,552,526 control chromosomes in the GnomAD database, including 14,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (979 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13061 hom.)
• Consequence: FLCN ENST00000389169.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.545
• Publications: 9 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=-0.84).
• BP6: Variant 17-17221311-C-T is Benign according to our data. Variant chr17-17221311-C-T is described in ClinVar as Benign. ClinVar VariationId is 1266988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.871+226G>A		intron_variant	Intron 8 of 13	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000389169.9	c.*68G>A		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000373821.5
FLCN	ENST00000285071.9	c.871+226G>A		intron_variant	Intron 8 of 13	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.149-2257G>A		intron_variant	Intron 4 of 11	1		ENSP00000394249.3
FLCN	ENST00000466317.1	n.940G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15910 AN: 152146 Hom.: 978 Cov.: 32

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.129

GnomAD4 exome AF: 0.132 AC: 185337 AN: 1400262 Hom.: 13061 Cov.: 32 AF XY: 0.133 AC XY: 91591 AN XY: 690966

African (AFR) AF: 0.0380 AC: 1204 AN: 31650

American (AMR) AF: 0.131 AC: 4696 AN: 35868

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 3885 AN: 25188

East Asian (EAS) AF: 0.000251 AC: 9 AN: 35798

South Asian (SAS) AF: 0.125 AC: 9897 AN: 79362

European-Finnish (FIN) AF: 0.117 AC: 5636 AN: 48358

Middle Eastern (MID) AF: 0.138 AC: 785 AN: 5698

European-Non Finnish (NFE) AF: 0.141 AC: 151954 AN: 1080224

Other (OTH) AF: 0.125 AC: 7271 AN: 58116

GnomAD4 genome AF: 0.105 AC: 15920 AN: 152264 Hom.: 979 Cov.: 32 AF XY: 0.105 AC XY: 7789 AN XY: 74450

African (AFR) AF: 0.0432 AC: 1794 AN: 41572

American (AMR) AF: 0.122 AC: 1867 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5192

South Asian (SAS) AF: 0.108 AC: 522 AN: 4818

European-Finnish (FIN) AF: 0.117 AC: 1237 AN: 10612

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9492 AN: 67992

Other (OTH) AF: 0.128 AC: 271 AN: 2114

Alfa AF: 0.129 Hom.: 519

Bravo AF: 0.103

Asia WGS AF: 0.0450 AC: 157 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.9
DANN	Benign	0.76
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs41400246; hg19: chr17-17124625; COSMIC: COSV53259379; COSMIC: COSV53259379;