rs757012294

Variant names:

• chr17-17227944-T-C
• NM_144997.7:c.194A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-17227944-T-C
• chr17-17227944-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_144997.7(FLCN):​c.194A>G​(p.Glu65Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.96

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]

ENSG00000264187 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 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
FLCN	NM_144997.7	c.194A>G	p.Glu65Gly	missense_variant	Exon 4 of 14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.194A>G	p.Glu65Gly	missense_variant	Exon 4 of 14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.148+46A>G		intron_variant	Intron 4 of 11	1		ENSP00000394249.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E65G variant (also known as c.194A>G), located in coding exon 1 of the FLCN gene, results from an A to G substitution at nucleotide position 194. The glutamic acid at codon 65 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Birt-Hogg-Dube syndrome Uncertain:1

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 65 of the FLCN protein (p.Glu65Gly). 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. ClinVar contains an entry for this variant (Variation ID: 2586509). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FLCN protein function with a negative predictive value of 80%. 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	Benign	0.091
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N;N;D
REVEL	Uncertain	0.57
Sift	Benign	0.16	T;D;D
Sift4G	Benign	0.17	T;T;T
Polyphen		0.039	B;D;.
Vest4		0.60
MutPred		0.18		Gain of MoRF binding (P = 0.0436);Gain of MoRF binding (P = 0.0436);.;
MVP		0.46
MPC		0.45
ClinPred		0.88	D
GERP RS		5.3
Varity_R		0.20
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-17131258;