Genetic Variant FLCN:c.-25+100C>G (chr17-17231694-G-C) – 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.-25+100C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.73 in 152,324 control chromosomes in the GnomAD database, including 41,076 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 41059 hom., cov: 35)

Exomes 𝑓: 0.71 ( 17 hom. )

Consequence

FLCN
NM_144997.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.36

Publications

5 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 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

FLCN links:

ENSG00000264187 (HGNC:):

ENSG00000264187 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=-0.96).

BP6

Variant 17-17231694-G-C is Benign according to our data. Variant chr17-17231694-G-C is described in ClinVar as Benign. ClinVar VariationId is 1251006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7 link	c.-25+100C>G		intron_variant	Intron 3 of 13	ENST00000285071.9	NP_659434.2	Q8NFG4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9 link	c.-25+100C>G		intron_variant	Intron 3 of 13	1	NM_144997.7	ENSP00000285071.4		Q8NFG4-1
ENSG00000264187	ENST00000427497.3 link	n.-25+100C>G		intron_variant	Intron 3 of 11	1		ENSP00000394249.3		J3QW42

Frequencies

GnomAD3 genomes

AF:

0.731

AC:

111134

AN:

152134

Hom.:

41051

Cov.:

show subpopulations

Gnomad AFR

AF:

0.639

Gnomad AMI

AF:

0.850

Gnomad AMR

AF:

0.738

Gnomad ASJ

AF:

0.735

Gnomad EAS

AF:

0.844

Gnomad SAS

AF:

0.726

Gnomad FIN

AF:

0.873

Gnomad MID

AF:

0.646

Gnomad NFE

AF:

0.753

Gnomad OTH

AF:

0.715

GnomAD4 exome

AF:

0.708

AC:

AN:

Hom.:

Cov.:

AF XY:

0.740

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.889

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.659

AC:

AN:

Other (OTH)

AF:

0.750

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.730

AC:

111185

AN:

152252

Hom.:

41059

Cov.:

AF XY:

0.736

AC XY:

54761

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.639

AC:

26519

AN:

41530

American (AMR)

AF:

0.737

AC:

11280

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.735

AC:

2551

AN:

3470

East Asian (EAS)

AF:

0.844

AC:

4372

AN:

5178

South Asian (SAS)

AF:

0.727

AC:

3515

AN:

4834

European-Finnish (FIN)

AF:

0.873

AC:

9269

AN:

10616

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.753

AC:

51209

AN:

68008

Other (OTH)

AF:

0.712

AC:

1505

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1579

3158

4736

6315

7894

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

846

1692

2538

3384

4230

<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:

0.747

Hom.:

5274

Bravo

AF:

0.720

Asia WGS

AF:

0.780

AC:

2711

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 22, 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

-0.96

CADD

Benign

0.30

(source)

DANN

Benign

0.49

PhyloP100

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over