17-17222647-CT-G

Variant names:

• chr17-17222647-CT-G
• rs879255661
• NM_144997.7:c.632_633delAGinsC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_144997.7(FLCN):​c.632_633delAGinsC​(p.Glu211AlafsTer12) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E211D) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN NM_144997.7 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.19
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-17222647-CT-G is Pathogenic according to our data. Variant chr17-17222647-CT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 253231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	NM_144997.7	MANE Select	c.632_633delAGinsC	p.Glu211AlafsTer12	frameshift missense	Exon 7 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.686_687delAGinsC	p.Glu229AlafsTer12	frameshift missense	Exon 9 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.632_633delAGinsC	p.Glu211AlafsTer12	frameshift missense	Exon 8 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.632_633delAGinsC	p.Glu211AlafsTer12	frameshift missense	Exon 7 of 14	ENSP00000285071.4
	FLCN	ENST00000389169.9	TSL:1	c.632_633delAGinsC	p.Glu211AlafsTer12	frameshift missense	Exon 7 of 8	ENSP00000373821.5
	ENSG00000264187	ENST00000427497.3	TSL:1	n.149-3594_149-3593delAGinsC		intron	N/A	ENSP00000394249.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:2

Sep 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jul 18, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Jul 07, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This combined deletion and insertion is denoted FLCN c.632_633delAGinsC at the cDNA level and p.Glu211AlafsX12 (E211AfsX12) at the protein level. The normal sequence, with the bases that are deleted and inserted in brackets, is GCAG[delAG][insC]CAGT. The variant causes a frameshift which changes a Glutamic Acid to an Alanine at codon 211, and creates a premature stop codon at position 12 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. FLCN c.632_633delAGinsC has been observed in association with Birt-Hogg-Dub? (Nickerson 2002, Schmidt 2005). We consider this variant to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879255661; hg19: chr17-17125961;