17-17226304-C-G

Position:

• chr17-17226304-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_144997.7(FLCN):​c.268G>C​(p.Ala90Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A90S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71

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.

• PM1: In a domain uDENN FLCN/SMCR8-type (size 156) in uniprot entity FLCN_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_144997.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26382908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.268G>C	p.Ala90Pro	missense_variant	5/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.268G>C	p.Ala90Pro	missense_variant	5/14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.148+1686G>C		intron_variant		1		ENSP00000394249.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.54	N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0	B;D;.
Vest4		0.31
MutPred		0.25		Loss of helix (P = 0.0138);Loss of helix (P = 0.0138);.;
MVP		0.32
MPC		0.48
ClinPred		0.62	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.35

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: chr17-17129618;