chr17-17227944-T-C

Variant names:

• chr17-17227944-T-C
• rs757012294
• NM_144997.7:c.194A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001353229.2(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E65A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLCN NM_001353229.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.96
• Publications: 0 publications found

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]

FLCN Gene-Disease associations (from GenCC):

• Birt-Hogg-Dube syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Birt-Hogg-Dube syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• familial spontaneous pneumothorax

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• renal carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264187 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353229.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	NM_144997.7	MANE Select	c.194A>G	p.Glu65Gly	missense	Exon 4 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.194A>G	p.Glu65Gly	missense	Exon 5 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.194A>G	p.Glu65Gly	missense	Exon 5 of 15	NP_001340159.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.194A>G	p.Glu65Gly	missense	Exon 4 of 14	ENSP00000285071.4
	FLCN	ENST00000389169.9	TSL:1	c.194A>G	p.Glu65Gly	missense	Exon 4 of 8	ENSP00000373821.5
	ENSG00000264187	ENST00000427497.3	TSL:1	n.148+46A>G		intron	N/A	ENSP00000394249.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Birt-Hogg-Dube syndrome (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.7	L
PhyloP100		7.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.57
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Polyphen		0.039	B
Vest4		0.60
MutPred		0.18		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

Other links and lift over

dbSNP: rs757012294; hg19: chr17-17131258;