Genetic Variant FLCN:p.Asp476Glu (chr17-17215189-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2BP6_Very_Strong

The NM_144997.7(FLCN):c.1428C>A(p.Asp476Glu) variant causes a missense 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D476N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

FLCN
NM_144997.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.45

Publications

0 publications found

Variant links:

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 links:

ENSG00000264187 (HGNC:):

ENSG00000264187 links:

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]

MPRIP links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 17-17215189-G-T is Benign according to our data. Variant chr17-17215189-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2445313.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLCN	NM_144997.7	MANE Select	c.1428C>A	p.Asp476Glu	missense	Exon 12 of 14	NP_659434.2
FLCN	NM_001353229.2		c.1482C>A	p.Asp494Glu	missense	Exon 14 of 16	NP_001340158.1
FLCN	NM_001353230.2		c.1428C>A	p.Asp476Glu	missense	Exon 13 of 15	NP_001340159.1	Q8NFG4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLCN	ENST00000285071.9	TSL:1 MANE Select	c.1428C>A	p.Asp476Glu	missense	Exon 12 of 14	ENSP00000285071.4	Q8NFG4-1
ENSG00000264187	ENST00000427497.3	TSL:1	n.*262C>A		non_coding_transcript_exon	Exon 8 of 12	ENSP00000394249.3	J3QW42
ENSG00000264187	ENST00000427497.3	TSL:1	n.*262C>A		3_prime_UTR	Exon 8 of 12	ENSP00000394249.3	J3QW42

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Birt-Hogg-Dube syndrome 1 (1)

Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.064

Eigen_PC

Benign

-0.0059

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-0.30

MutationAssessor

Benign

2.0

PhyloP100

1.4

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.54

REVEL

Uncertain

0.38

Sift

Benign

0.19

Sift4G

Benign

0.55

Polyphen

0.92

Vest4

0.66

MutPred

0.43

Loss of stability (P = 0.059)

MVP

0.35

MPC

0.35

ClinPred

0.46

GERP RS

1.6

Varity_R

0.17

gMVP

0.33

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over