rs2291563

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001458.5(FLNC):c.1458C>A(p.Pro486Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0454 in 1,614,004 control chromosomes in the GnomAD database, including 6,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 2349 hom., cov: 33)

Exomes 𝑓: 0.038 ( 4338 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.119

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics, G2P
myofibrillar myopathy 5
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
hypertrophic cardiomyopathy 26
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
distal myopathy with posterior leg and anterior hand involvement
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
familial isolated restrictive cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
heart conduction disease
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

FLNC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 7-128840069-C-A is Benign according to our data. Variant chr7-128840069-C-A is described in CliVar as Benign. Clinvar id is 129080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128840069-C-A is described in CliVar as Benign. Clinvar id is 129080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128840069-C-A is described in CliVar as Benign. Clinvar id is 129080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128840069-C-A is described in CliVar as Benign. Clinvar id is 129080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128840069-C-A is described in CliVar as Benign. Clinvar id is 129080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128840069-C-A is described in CliVar as Benign. Clinvar id is 129080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128840069-C-A is described in CliVar as Benign. Clinvar id is 129080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128840069-C-A is described in CliVar as Benign. Clinvar id is 129080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.119 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5 link	c.1458C>A	p.Pro486Pro	synonymous_variant	Exon 9 of 48	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 link	c.1458C>A	p.Pro486Pro	synonymous_variant	Exon 9 of 47		NP_001120959.1	Q14315-2Q59H94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 link	c.1458C>A	p.Pro486Pro	synonymous_variant	Exon 9 of 48	1	NM_001458.5	ENSP00000327145.8		Q14315-1

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17700

AN:

152176

Hom.:

2343

Cov.:

show subpopulations

Gnomad AFR

AF:

0.308

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0842

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.302

Gnomad SAS

AF:

0.0794

Gnomad FIN

AF:

0.0197

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0175

Gnomad OTH

AF:

0.0985

GnomAD2 exomes

AF:

0.0814

AC:

20301

AN:

249396

AF XY:

0.0733

show subpopulations

Gnomad AFR exome

AF:

0.311

Gnomad AMR exome

AF:

0.127

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.321

Gnomad FIN exome

AF:

0.0257

Gnomad NFE exome

AF:

0.0182

Gnomad OTH exome

AF:

0.0541

GnomAD4 exome

AF:

0.0381

AC:

55618

AN:

1461710

Hom.:

4338

Cov.:

AF XY:

0.0378

AC XY:

27485

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.309

AC:

10349

AN:

33480

American (AMR)

AF:

0.123

AC:

5500

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0252

AC:

658

AN:

26136

East Asian (EAS)

AF:

0.280

AC:

11126

AN:

39696

South Asian (SAS)

AF:

0.0701

AC:

6047

AN:

86252

European-Finnish (FIN)

AF:

0.0256

AC:

1362

AN:

53266

Middle Eastern (MID)

AF:

0.0310

AC:

179

AN:

5768

European-Non Finnish (NFE)

AF:

0.0153

AC:

17021

AN:

1111998

Other (OTH)

AF:

0.0559

AC:

3376

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

3066

6131

9197

12262

15328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

992

1984

2976

3968

4960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.116

AC:

17732

AN:

152294

Hom.:

2349

Cov.:

AF XY:

0.116

AC XY:

8603

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.308

AC:

12794

AN:

41532

American (AMR)

AF:

0.0839

AC:

1285

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0265

AC:

AN:

3470

East Asian (EAS)

AF:

0.301

AC:

1557

AN:

5174

South Asian (SAS)

AF:

0.0789

AC:

381

AN:

4830

European-Finnish (FIN)

AF:

0.0197

AC:

209

AN:

10628

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0176

AC:

1194

AN:

68030

Other (OTH)

AF:

0.0993

AC:

210

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

691

1382

2074

2765

3456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0561

Hom.:

990

Bravo

AF:

0.132

Asia WGS

AF:

0.178

AC:

619

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0163

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 12, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Pro486Pro in exon 9 of FLNC: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 28.9% (1144/3952) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2291563). -

Apr 10, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 13, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 26, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

0.12

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over