rs370512642

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_001458.5(FLNC):c.31G>A(p.Gly11Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000322 in 1,612,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G11C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.75

Variant links:

Genes affected

FLNC (HGNC:3756): (filamin C) This gene encodes one of three related filamin genes, specifically gamma filamin. These filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. Three functional domains exist in filamin: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. Mutations in this gene are a cause of cardiopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2022]

FLNC links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant where missense usually causes diseases, FLNC

BP4

Computational evidence support a benign effect (MetaRNN=0.039979488).

BP6

Variant 7-128830668-G-A is Benign according to our data. Variant chr7-128830668-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539388.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr7-128830668-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.31G>A	p.Gly11Ser	missense_variant	1/48	ENST00000325888.13
FLNC	NM_001127487.2 linkuse as main transcript	c.31G>A	p.Gly11Ser	missense_variant	1/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.31G>A	p.Gly11Ser	missense_variant	1/48	1	NM_001458.5	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.31G>A	p.Gly11Ser	missense_variant	1/47	1		A1	Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000571

AC:

AN:

245298

Hom.:

AF XY:

0.0000447

AC XY:

AN XY:

134186

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.0000873

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1460224

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726408

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000177

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000225

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000912

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000992

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2022

The p.G11S variant (also known as c.31G>A), located in coding exon 1 of the FLNC gene, results from a G to A substitution at nucleotide position 31. The glycine at codon 11 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2020

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 539388; Landrum et al., 2016) -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.28

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.066

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.67

T;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.040

T;T

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.2

L;L

MutationTaster

Benign

0.51

N;N

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.51

N;N

REVEL

Benign

0.21

Sift

Benign

0.13

T;T

Sift4G

Benign

0.48

T;T

Polyphen

0.043

B;B

Vest4

0.27

MVP

0.55

MPC

1.0

ClinPred

0.035

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.042

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over