17-17228073-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_144997.7(FLCN):​c.65C>G​(p.Thr22Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

FLCN
NM_144997.7 missense

Scores

12
5
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.26
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLCNNM_144997.7 linkc.65C>G p.Thr22Arg missense_variant Exon 4 of 14 ENST00000285071.9 NP_659434.2 Q8NFG4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLCNENST00000285071.9 linkc.65C>G p.Thr22Arg missense_variant Exon 4 of 14 1 NM_144997.7 ENSP00000285071.4 Q8NFG4-1
ENSG00000264187ENST00000427497.3 linkn.65C>G non_coding_transcript_exon_variant Exon 4 of 12 1 ENSP00000394249.3 J3QW42

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Birt-Hogg-Dube syndrome Uncertain:1
Jan 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 22 of the FLCN protein (p.Thr22Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLCN-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FLCN protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
34
DANN
Benign
0.95
DEOGEN2
Pathogenic
0.86
D;.;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.94
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.3
M;M;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-4.5
D;D;.
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0050
D;D;.
Sift4G
Uncertain
0.010
D;D;.
Polyphen
1.0
D;D;.
Vest4
0.99
MutPred
0.78
Gain of disorder (P = 0.1336);Gain of disorder (P = 0.1336);Gain of disorder (P = 0.1336);
MVP
0.92
MPC
1.2
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.93
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.54
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.54
Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-17131387; API