rs2292527

Variant names:

• chr17-17222727-G-A
• rs2292527
• NM_144997.7:c.619-66C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-17222727-G-A
• chr17-17222727-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144997.7(FLCN):​c.619-66C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0454 in 1,600,496 control chromosomes in the GnomAD database, including 2,774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (198 hom., cov: 32)
  • Exomes 𝑓: 0.046 (2576 hom.)
• Consequence: FLCN NM_144997.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.46
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 17-17222727-G-A is Benign according to our data. Variant chr17-17222727-G-A is described in ClinVar as Benign. ClinVar VariationId is 1245008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.619-66C>T		intron_variant	Intron 6 of 13	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.619-66C>T		intron_variant	Intron 6 of 13	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.149-3673C>T		intron_variant	Intron 4 of 11	1		ENSP00000394249.3

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5862 AN: 152082 Hom.: 200 Cov.: 32

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0350

Gnomad OTH AF: 0.0316

GnomAD4 exome AF: 0.0461 AC: 66809 AN: 1448296 Hom.: 2576 Cov.: 27 AF XY: 0.0493 AC XY: 35552 AN XY: 720920

African (AFR) AF: 0.0211 AC: 702 AN: 33240

American (AMR) AF: 0.0424 AC: 1866 AN: 44012

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 538 AN: 26014

East Asian (EAS) AF: 0.148 AC: 5855 AN: 39530

South Asian (SAS) AF: 0.155 AC: 13258 AN: 85262

European-Finnish (FIN) AF: 0.0261 AC: 1375 AN: 52678

Middle Eastern (MID) AF: 0.0258 AC: 148 AN: 5734

European-Non Finnish (NFE) AF: 0.0365 AC: 40256 AN: 1101924

Other (OTH) AF: 0.0469 AC: 2811 AN: 59902

GnomAD4 genome AF: 0.0386 AC: 5875 AN: 152200 Hom.: 198 Cov.: 32 AF XY: 0.0404 AC XY: 3007 AN XY: 74404

African (AFR) AF: 0.0218 AC: 907 AN: 41530

American (AMR) AF: 0.0395 AC: 604 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3468

East Asian (EAS) AF: 0.141 AC: 730 AN: 5164

South Asian (SAS) AF: 0.162 AC: 782 AN: 4818

European-Finnish (FIN) AF: 0.0263 AC: 279 AN: 10614

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0350 AC: 2378 AN: 67998

Other (OTH) AF: 0.0346 AC: 73 AN: 2108

Alfa AF: 0.0375 Hom.: 220

Bravo AF: 0.0352

Asia WGS AF: 0.124 AC: 431 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.22
DANN	Benign	0.40
PhyloP100		-3.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs2292527; hg19: chr17-17126041; COSMIC: COSV53258124; COSMIC: COSV53258124;