17-17217071-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_144997.7(FLCN):c.1174C>G(p.Arg392Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R392W) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

FLCN
NM_144997.7 missense, splice_region

Scores

Splicing: ADA: 0.1323

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.32

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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	HGVSp	Effect	Exon Rank	Protein
FLCN	NM_144997.7	MANE Select	c.1174C>G	p.Arg392Gly	missense splice_region	Exon 10 of 14	NP_659434.2
FLCN	NM_001353229.2		c.1228C>G	p.Arg410Gly	missense splice_region	Exon 12 of 16	NP_001340158.1
FLCN	NM_001353230.2		c.1174C>G	p.Arg392Gly	missense splice_region	Exon 11 of 15	NP_001340159.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLCN	ENST00000285071.9	TSL:1 MANE Select	c.1174C>G	p.Arg392Gly	missense splice_region	Exon 10 of 14	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	TSL:1	n.*8C>G		splice_region non_coding_transcript_exon	Exon 6 of 12	ENSP00000394249.3
ENSG00000264187	ENST00000427497.3	TSL:1	n.*8C>G		3_prime_UTR	Exon 6 of 12	ENSP00000394249.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250992

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Birt-Hogg-Dube syndrome

Uncertain:1

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 392 of the FLCN protein (p.Arg392Gly). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with FLCN-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Benign

-0.069

Eigen_PC

Benign

0.076

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.74

MetaSVM

Uncertain

-0.044

MutationAssessor

Benign

1.4

PhyloP100

3.3

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.55

Sift

Uncertain

0.021

Sift4G

Uncertain

0.016

Polyphen

0.21

Vest4

0.68

MutPred

0.60

Gain of loop (P = 0.069)

MVP

0.62

MPC

0.51

ClinPred

0.86

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.56

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.13

dbscSNV1_RF

Benign

0.31

SpliceAI score (max)

0.030

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over