GeneBe

rs200168437

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.592G>T​(p.Asp198Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. D198N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

FLCN
NM_144997.7 missense

Scores

2
13
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.75

Publications

0 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

Genome browser will be placed here

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;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLCNNM_144997.7 linkc.592G>T p.Asp198Tyr missense_variant Exon 6 of 14 ENST00000285071.9 NP_659434.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLCNENST00000285071.9 linkc.592G>T p.Asp198Tyr missense_variant Exon 6 of 14 1 NM_144997.7 ENSP00000285071.4
ENSG00000264187ENST00000427497.3 linkn.148+4042G>T intron_variant Intron 4 of 11 1 ENSP00000394249.3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461056
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726838
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86248
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112004
Other (OTH)
AF:
0.00
AC:
0
AN:
60384
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
May 27, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1
Mar 23, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.D198Y variant (also known as c.592G>T), located in coding exon 3 of the FLCN gene, results from a G to T substitution at nucleotide position 592. The aspartic acid at codon 198 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.77
D;.;D
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.54
D;D;D
MetaSVM
Uncertain
0.30
D
MutationAssessor
Benign
1.1
L;L;.
PhyloP100
4.8
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-2.3
N;N;N
REVEL
Pathogenic
0.65
Sift
Uncertain
0.021
D;T;D
Sift4G
Uncertain
0.026
D;D;D
Polyphen
0.57
P;P;.
Vest4
0.63
MutPred
0.40
Gain of methylation at R194 (P = 0.0551);Gain of methylation at R194 (P = 0.0551);.;
MVP
0.66
MPC
0.82
ClinPred
0.96
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.70
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs200168437; hg19: chr17-17127262; COSMIC: COSV105130044; COSMIC: COSV105130044; API