rs757060348

Variant names:

• chr17-17227891-C-T
• rs757060348
• NM_144997.7:c.247G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-17227891-C-T
• chr17-17227891-C-A
• chr17-17227891-C-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_144997.7(FLCN):​c.247G>A​(p.Glu83Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000167 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: FLCN NM_144997.7 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 6.68
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 17-17227891-C-T is Benign according to our data. Variant chr17-17227891-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 390184.
• BS2: High AC in GnomAdExome4 at 24 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.247G>A	p.Glu83Lys	missense splice_region	Exon 4 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.247G>A	p.Glu83Lys	missense splice_region	Exon 5 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.247G>A	p.Glu83Lys	missense splice_region	Exon 5 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.247G>A	p.Glu83Lys	missense splice_region	Exon 4 of 14	ENSP00000285071.4	Q8NFG4-1
	FLCN	ENST00000389169.9	TSL:1	c.247G>A	p.Glu83Lys	missense splice_region	Exon 4 of 8	ENSP00000373821.5	Q8NFG4-2
	ENSG00000264187	ENST00000427497.3	TSL:1	n.148+99G>A		intron	N/A	ENSP00000394249.3	J3QW42

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250784 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727184

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1112000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	2.0	M
PhyloP100		6.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.55
Sift	Benign	0.064	T
Sift4G	Benign	0.31	T
Polyphen		0.060	B
Vest4		0.80
MutPred		0.33		Gain of methylation at E83 (P = 5e-04)
MVP		0.34
MPC		0.42
ClinPred		0.70	D
GERP RS		5.5
Varity_R		0.34
gMVP		0.52
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs757060348; hg19: chr17-17131205; COSMIC: COSV53258292; COSMIC: COSV53258292;