rs138070947

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The ENST00000285071.9(FLCN):​c.580C>T​(p.Arg194Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,613,342 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R194Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

FLCN
ENST00000285071.9 missense

Scores

3
13
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 3.52
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6
Variant 17-17223960-G-A is Benign according to our data. Variant chr17-17223960-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141552.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}.
BS2
High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FLCNNM_144997.7 linkuse as main transcriptc.580C>T p.Arg194Trp missense_variant 6/14 ENST00000285071.9 NP_659434.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FLCNENST00000285071.9 linkuse as main transcriptc.580C>T p.Arg194Trp missense_variant 6/141 NM_144997.7 ENSP00000285071 P1Q8NFG4-1
FLCNENST00000389169.9 linkuse as main transcriptc.580C>T p.Arg194Trp missense_variant 6/81 ENSP00000373821 Q8NFG4-2
FLCNENST00000417064.1 linkuse as main transcriptc.421C>T p.Arg141Trp missense_variant 4/42 ENSP00000410410
FLCNENST00000480316.1 linkuse as main transcriptn.546C>T non_coding_transcript_exon_variant 1/32

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000192
AC:
48
AN:
250438
Hom.:
0
AF XY:
0.000192
AC XY:
26
AN XY:
135666
show subpopulations
Gnomad AFR exome
AF:
0.0000619
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000294
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000319
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000197
AC:
288
AN:
1461154
Hom.:
1
Cov.:
32
AF XY:
0.000216
AC XY:
157
AN XY:
726884
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000255
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000228
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152188
Hom.:
0
Cov.:
33
AF XY:
0.000202
AC XY:
15
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.000145
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000312
Hom.:
0
Bravo
AF:
0.000196
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000698
AC:
6
ExAC
AF:
0.000198
AC:
24
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 01, 2019This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Mar 05, 2022- -
Birt-Hogg-Dube syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaJul 18, 2016- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalJul 31, 2024- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 10, 2021In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal history of advanced cancer (Mandelker 2017); This variant is associated with the following publications: (PMID: 29109099, 29181861, 28873162) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Benign
-0.024
T
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
D;.;D
Eigen
Uncertain
0.68
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Uncertain
0.59
D;D;D
MetaSVM
Uncertain
0.55
D
MutationAssessor
Benign
1.8
L;L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.8
D;D;D
REVEL
Uncertain
0.58
Sift
Uncertain
0.0080
D;D;D
Sift4G
Uncertain
0.018
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.66
MVP
0.69
MPC
1.2
ClinPred
0.25
T
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.79
gMVP
0.80

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138070947; hg19: chr17-17127274; COSMIC: COSV53256861; COSMIC: COSV53256861; API