rs2291568

Positions:

chr7-128847839-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001458.5(FLNC):c.4431G>A(p.Leu1477=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.076 in 1,613,544 control chromosomes in the GnomAD database, including 11,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 3591 hom., cov: 34)

Exomes 𝑓: 0.068 ( 7902 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.313

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 7-128847839-G-A is Benign according to our data. Variant chr7-128847839-G-A is described in ClinVar as [Benign]. Clinvar id is 129090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128847839-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.313 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.373 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.4431G>A	p.Leu1477=	synonymous_variant	25/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2 linkuse as main transcript	c.4431G>A	p.Leu1477=	synonymous_variant	25/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.4431G>A	p.Leu1477=	synonymous_variant	25/48	1	NM_001458.5	ENSP00000327145	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.4431G>A	p.Leu1477=	synonymous_variant	25/47	1		ENSP00000344002	A1	Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

23559

AN:

152138

Hom.:

3584

Cov.:

show subpopulations

Gnomad AFR

AF:

0.378

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.352

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.0214

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0423

Gnomad OTH

AF:

0.120

GnomAD3 exomes

AF:

0.117

AC:

29165

AN:

248632

Hom.:

3442

AF XY:

0.111

AC XY:

14970

AN XY:

134974

show subpopulations

Gnomad AFR exome

AF:

0.381

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.0182

Gnomad EAS exome

AF:

0.362

Gnomad SAS exome

AF:

0.170

Gnomad FIN exome

AF:

0.0267

Gnomad NFE exome

AF:

0.0436

Gnomad OTH exome

AF:

0.0874

GnomAD4 exome

AF:

0.0678

AC:

99122

AN:

1461290

Hom.:

7902

Cov.:

AF XY:

0.0693

AC XY:

50397

AN XY:

726938

show subpopulations

Gnomad4 AFR exome

AF:

0.381

Gnomad4 AMR exome

AF:

0.154

Gnomad4 ASJ exome

AF:

0.0182

Gnomad4 EAS exome

AF:

0.334

Gnomad4 SAS exome

AF:

0.167

Gnomad4 FIN exome

AF:

0.0277

Gnomad4 NFE exome

AF:

0.0400

Gnomad4 OTH exome

AF:

0.0852

GnomAD4 genome

AF:

0.155

AC:

23583

AN:

152254

Hom.:

3591

Cov.:

AF XY:

0.154

AC XY:

11477

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.378

Gnomad4 AMR

AF:

0.116

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.352

Gnomad4 SAS

AF:

0.182

Gnomad4 FIN

AF:

0.0214

Gnomad4 NFE

AF:

0.0423

Gnomad4 OTH

AF:

0.120

Alfa

AF:

0.0605

Hom.:

733

Bravo

AF:

0.172

Asia WGS

AF:

0.265

AC:

920

AN:

3478

EpiCase

AF:

0.0397

EpiControl

AF:

0.0434

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
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	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	PreventionGenetics, part of Exact Sciences	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Leu1477Leu in exon 25 of FLNC: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 35.4% (1352/3822) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2291568). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 21, 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 24, 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

-0.49

CADD

Benign

DANN

Benign

0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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