Genetic Variant FLCN:c.1176+31G>A (chr17-17217038-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144997.7(FLCN):c.1176+31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,502,228 control chromosomes in the GnomAD database, including 438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 42 hom., cov: 33)

Exomes 𝑓: 0.019 ( 396 hom. )

Consequence

FLCN
NM_144997.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.123

Publications

3 publications found

Variant links:

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 links:

ENSG00000264187 (HGNC:):

ENSG00000264187 links:

MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

MPRIP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 17-17217038-C-T is Benign according to our data. Variant chr17-17217038-C-T is described in ClinVar as Benign. ClinVar VariationId is 496848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0603 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FLCN	NM_144997.7	MANE Select	c.1176+31G>A	intron	N/A	NP_659434.2
FLCN	NM_001353229.2		c.1230+31G>A	intron	N/A	NP_001340158.1
FLCN	NM_001353230.2		c.1176+31G>A	intron	N/A	NP_001340159.1	Q8NFG4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FLCN	ENST00000285071.9	TSL:1 MANE Select	c.1176+31G>A	intron	N/A	ENSP00000285071.4	Q8NFG4-1
ENSG00000264187	ENST00000427497.3	TSL:1	n.*10+31G>A	intron	N/A	ENSP00000394249.3	J3QW42
FLCN	ENST00000962729.1		c.1281+31G>A	intron	N/A	ENSP00000632788.1

Frequencies

GnomAD3 genomes

AF:

0.0158

AC:

2398

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0379

Gnomad ASJ

AF:

0.0205

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0432

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0186

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.0247

AC:

6161

AN:

249196

AF XY:

0.0251

show subpopulations

Gnomad AFR exome

AF:

0.00315

Gnomad AMR exome

AF:

0.0646

Gnomad ASJ exome

AF:

0.0158

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0115

Gnomad NFE exome

AF:

0.0178

Gnomad OTH exome

AF:

0.0195

GnomAD4 exome

AF:

0.0193

AC:

26112

AN:

1349952

Hom.:

396

Cov.:

AF XY:

0.0200

AC XY:

13555

AN XY:

677822

show subpopulations

African (AFR)

AF:

0.00247

AC:

AN:

31152

American (AMR)

AF:

0.0623

AC:

2770

AN:

44486

Ashkenazi Jewish (ASJ)

AF:

0.0157

AC:

399

AN:

25426

East Asian (EAS)

AF:

0.000102

AC:

AN:

39176

South Asian (SAS)

AF:

0.0445

AC:

3736

AN:

83900

European-Finnish (FIN)

AF:

0.0105

AC:

559

AN:

53154

Middle Eastern (MID)

AF:

0.0245

AC:

135

AN:

5520

European-Non Finnish (NFE)

AF:

0.0174

AC:

17547

AN:

1010512

Other (OTH)

AF:

0.0156

AC:

885

AN:

56626

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1349

2698

4048

5397

6746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

678

1356

2034

2712

3390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0157

AC:

2397

AN:

152276

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1231

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00298

AC:

124

AN:

41558

American (AMR)

AF:

0.0379

AC:

579

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

AN:

3470

East Asian (EAS)

AF:

0.000773

AC:

AN:

5174

South Asian (SAS)

AF:

0.0432

AC:

208

AN:

4816

European-Finnish (FIN)

AF:

0.0103

AC:

109

AN:

10618

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0186

AC:

1262

AN:

68030

Other (OTH)

AF:

0.0137

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

123

246

369

492

615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0158

Hom.:

Bravo

AF:

0.0160

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.7

(source)

DANN

Benign

0.53

PhyloP100

-0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over