rs878855221

Variant names:

• chr17-17219093-AG-A
• rs878855221
• NM_144997.7:c.987delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_144997.7(FLCN):​c.987delC​(p.Ser330ProfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S329S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FLCN NM_144997.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.31
• Publications: 2 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 12 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 17-17219093-AG-A is Pathogenic according to our data. Variant chr17-17219093-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 241933.Status of the report is criteria_provided_single_submitter, 1 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.987delC	p.Ser330ProfsTer23	frameshift	Exon 9 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.1041delC	p.Ser348ProfsTer23	frameshift	Exon 11 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.987delC	p.Ser330ProfsTer23	frameshift	Exon 10 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.987delC	p.Ser330ProfsTer23	frameshift	Exon 9 of 14	ENSP00000285071.4
	ENSG00000264187	ENST00000427497.3	TSL:1	n.149-40delC		intron	N/A	ENSP00000394249.3
	FLCN	ENST00000577591.1	TSL:2	n.10delC		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:1

Sep 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 241933). This variant has not been reported in the literature in individuals affected with FLCN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser330Profs*23) in the FLCN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs878855221; hg19: chr17-17122407;