17-17227930-C-G

Position:

• chr17-17227930-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_144997.7(FLCN):​c.208G>C​(p.Glu70Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. E70K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:1
• Conservation: PhyloP100: 5.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3492676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7	c.208G>C	p.Glu70Gln	missense_variant	4/14	ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9	c.208G>C	p.Glu70Gln	missense_variant	4/14	1	NM_144997.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birt-Hogg-Dube syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 24, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 70 of the FLCN protein (p.Glu70Gln). 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 not expected to disrupt FLCN protein function. 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	0.12
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.62	N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.30	T;T;D
Sift4G	Benign	0.57	T;T;T
Polyphen		0.039	B;P;.
Vest4		0.16
MutPred		0.075		Gain of MoRF binding (P = 0.0744);Gain of MoRF binding (P = 0.0744);.;
MVP		0.55
MPC		0.43
ClinPred		0.65	D
GERP RS		5.5
Varity_R		0.084
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-17131244;