chr17-17216935-C-G

Position:

• chr17-17216935-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144997.7(FLCN):​c.1176+134G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 731,558 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (159 hom., cov: 33)
  • Exomes 𝑓: 0.021 (188 hom.)
• Consequence: FLCN NM_144997.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.921

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]

ENSG00000264187 (HGNC:):

MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-17216935-C-G is Benign according to our data. Variant chr17-17216935-C-G is described in ClinVar as [Benign]. Clinvar id is 1292842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17216935-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1176+134G>C		intron_variant		ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1176+134G>C		intron_variant		1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.*10+134G>C		intron_variant		1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-555C>G		intron_variant		3		ENSP00000464276.1
FLCN	ENST00000577591.1	n.*37G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5340 AN: 152156 Hom.: 160 Cov.: 33

Gnomad AFR AF: 0.0773

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0306

GnomAD4 exome AF: 0.0215 AC: 12430 AN: 579284 Hom.: 188 Cov.: 7 AF XY: 0.0210 AC XY: 6504 AN XY: 310386

Gnomad4 AFR exome AF: 0.0800

Gnomad4 AMR exome AF: 0.0134

Gnomad4 ASJ exome AF: 0.0300

Gnomad4 EAS exome AF: 0.00938

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.00468

Gnomad4 NFE exome AF: 0.0217

Gnomad4 OTH exome AF: 0.0254

GnomAD4 genome AF: 0.0351 AC: 5342 AN: 152274 Hom.: 159 Cov.: 33 AF XY: 0.0341 AC XY: 2536 AN XY: 74462

Gnomad4 AFR AF: 0.0772

Gnomad4 AMR AF: 0.0198

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.0188

Gnomad4 FIN AF: 0.00236

Gnomad4 NFE AF: 0.0223

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.00324 Hom.: 0

Bravo AF: 0.0375

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.1
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs41371953; hg19: chr17-17120249;