rs2291569

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001458.5(FLNC):c.4700G>A(p.Arg1567Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0819 in 1,613,300 control chromosomes in the GnomAD database, including 5,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.064 ( 400 hom., cov: 33)

Exomes 𝑓: 0.084 ( 5375 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.51

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNC. . Gene score misZ 2.789 (greater than the threshold 3.09). Trascript score misZ 5.9457 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, heart conduction disease, familial isolated restrictive cardiomyopathy, hypertrophic cardiomyopathy 26, distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5.

BP4

Computational evidence support a benign effect (MetaRNN=0.008130968).

BP6

Variant 7-128848680-G-A is Benign according to our data. Variant chr7-128848680-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128848680-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.4700G>A	p.Arg1567Gln	missense_variant	27/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2 linkuse as main transcript	c.4700G>A	p.Arg1567Gln	missense_variant	27/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.4700G>A	p.Arg1567Gln	missense_variant	27/48	1	NM_001458.5	ENSP00000327145	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.4700G>A	p.Arg1567Gln	missense_variant	27/47	1		ENSP00000344002	A1	Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.0645

AC:

9812

AN:

152136

Hom.:

401

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0224

Gnomad AMI

AF:

0.0789

Gnomad AMR

AF:

0.0437

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.0901

Gnomad FIN

AF:

0.0631

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0863

Gnomad OTH

AF:

0.0809

GnomAD3 exomes

AF:

0.0750

AC:

18657

AN:

248650

Hom.:

793

AF XY:

0.0778

AC XY:

10508

AN XY:

134990

show subpopulations

Gnomad AFR exome

AF:

0.0189

Gnomad AMR exome

AF:

0.0344

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.0970

Gnomad SAS exome

AF:

0.0830

Gnomad FIN exome

AF:

0.0687

Gnomad NFE exome

AF:

0.0870

Gnomad OTH exome

AF:

0.0866

GnomAD4 exome

AF:

0.0837

AC:

122286

AN:

1461046

Hom.:

5375

Cov.:

AF XY:

0.0842

AC XY:

61197

AN XY:

726874

show subpopulations

Gnomad4 AFR exome

AF:

0.0192

Gnomad4 AMR exome

AF:

0.0373

Gnomad4 ASJ exome

AF:

0.104

Gnomad4 EAS exome

AF:

0.127

Gnomad4 SAS exome

AF:

0.0841

Gnomad4 FIN exome

AF:

0.0710

Gnomad4 NFE exome

AF:

0.0862

Gnomad4 OTH exome

AF:

0.0823

GnomAD4 genome

AF:

0.0645

AC:

9820

AN:

152254

Hom.:

400

Cov.:

AF XY:

0.0632

AC XY:

4705

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0223

Gnomad4 AMR

AF:

0.0435

Gnomad4 ASJ

AF:

0.115

Gnomad4 EAS

AF:

0.114

Gnomad4 SAS

AF:

0.0906

Gnomad4 FIN

AF:

0.0631

Gnomad4 NFE

AF:

0.0863

Gnomad4 OTH

AF:

0.0838

Alfa

AF:

0.0838

Hom.:

980

Bravo

AF:

0.0610

TwinsUK

AF:

0.0895

AC:

332

ALSPAC

AF:

0.0893

AC:

344

ESP6500AA

AF:

0.0244

AC:

102

ESP6500EA

AF:

0.0850

AC:

716

ExAC

AF:

0.0762

AC:

9219

Asia WGS

AF:

0.103

AC:

360

AN:

3478

EpiCase

AF:

0.0907

EpiControl

AF:

0.0887

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Arg1567Gln in exon 27 of FLNC: This variant is not expected to have clinical s ignificance because it has been identified in 8.5% (716/8422) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs2291569). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

D;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.0081

T;T

MetaSVM

Benign

-0.47

MutationAssessor

Pathogenic

3.0

M;M

MutationTaster

Benign

0.00062

P;P

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.067

T;D

Sift4G

Uncertain

0.028

D;D

Polyphen

0.91

P;D

Vest4

0.18

MPC

1.0

ClinPred

0.074

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.43

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