rs2291563

Positions:

chr7-128840069-C-A

Variant summary

Our verdict is Benign. Variant got -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:12

Conservation

PhyloP100: 0.119

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 -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 ClinVar 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 Lovd as [Benign].

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/exons	MANE	Protein	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.1458C>A	p.Pro486Pro	synonymous_variant	9/48	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 linkuse as main transcript	c.1458C>A	p.Pro486Pro	synonymous_variant	9/47		NP_001120959.1	Q14315-2Q59H94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.1458C>A	p.Pro486Pro	synonymous_variant	9/48	1	NM_001458.5	ENSP00000327145.8		Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.1458C>A	p.Pro486Pro	synonymous_variant	9/47	1		ENSP00000344002.6		Q14315-2

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

GnomAD3 exomes

AF:

0.0814

AC:

20301

AN:

249396

Hom.:

2190

AF XY:

0.0733

AC XY:

9923

AN XY:

135358

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 SAS exome

AF:

0.0699

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

Gnomad4 AFR exome

AF:

0.309

Gnomad4 AMR exome

AF:

0.123

Gnomad4 ASJ exome

AF:

0.0252

Gnomad4 EAS exome

AF:

0.280

Gnomad4 SAS exome

AF:

0.0701

Gnomad4 FIN exome

AF:

0.0256

Gnomad4 NFE exome

AF:

0.0153

Gnomad4 OTH exome

AF:

0.0559

GnomAD4 genome

AF:

0.116

AC:

17732

AN:

152294

Hom.:

2349

Cov.:

AF XY:

0.116

AC XY:

8603

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.308

Gnomad4 AMR

AF:

0.0839

Gnomad4 ASJ

AF:

0.0265

Gnomad4 EAS

AF:

0.301

Gnomad4 SAS

AF:

0.0789

Gnomad4 FIN

AF:

0.0197

Gnomad4 NFE

AF:

0.0176

Gnomad4 OTH

AF:

0.0993

Alfa

AF:

0.0553

Hom.:

679

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	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). -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 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 26, 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

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.76

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