NM_144997.7:c.715C>T

Variant names:

• chr17-17222565-G-A
• rs78683075
• NM_144997.7:c.715C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_144997.7(FLCN):​c.715C>T​(p.Arg239Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000438 in 1,614,232 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R239H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:7 O:1
• Conservation: PhyloP100: 7.11
• Publications: 23 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, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, Ambry Genetics, Genomics England PanelApp
• 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: Benign. The variant received -8 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811
• BP6: Variant 17-17222565-G-A is Benign according to our data. Variant chr17-17222565-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134427.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000458 (669/1461890) while in subpopulation NFE AF = 0.000567 (631/1112012). AF 95% confidence interval is 0.00053. There are 1 homozygotes in GnomAdExome4. There are 334 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 38 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144997.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	NM_144997.7	MANE Select	c.715C>T	p.Arg239Cys	missense	Exon 7 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.769C>T	p.Arg257Cys	missense	Exon 9 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.715C>T	p.Arg239Cys	missense	Exon 8 of 15	NP_001340159.1	Q8NFG4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.715C>T	p.Arg239Cys	missense	Exon 7 of 14	ENSP00000285071.4	Q8NFG4-1
	FLCN	ENST00000389169.9	TSL:1	c.715C>T	p.Arg239Cys	missense	Exon 7 of 8	ENSP00000373821.5	Q8NFG4-2
	ENSG00000264187	ENST00000427497.3	TSL:1	n.149-3511C>T		intron	N/A	ENSP00000394249.3	J3QW42

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000259 AC: 65 AN: 251378 AF XY: 0.000228

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000458 AC: 669 AN: 1461890 Hom.: 1 Cov.: 31 AF XY: 0.000459 AC XY: 334 AN XY: 727246

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000567 AC: 631 AN: 1112012

Other (OTH) AF: 0.000348 AC: 21 AN: 60396

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74500

African (AFR) AF: 0.0000722 AC: 3 AN: 41568

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000447 Hom.: 0

Bravo AF: 0.000230

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000709

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	Birt-Hogg-Dube syndrome (5)
-	4	1	not provided (5)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	1	not specified (3)
-	-	1	FLCN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MVP		0.93
MPC		1.4
ClinPred		0.41	T
GERP RS		5.7
Varity_R		0.84
gMVP		0.81
Mutation Taster		=49/51	disease causing

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: rs78683075; hg19: chr17-17125879; COSMIC: COSV104533887;