rs2291561

Positions:

chr7-128837493-T-C

Variant summary

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

The NM_001458.5(FLNC):c.795T>C(p.Gly265=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,614,090 control chromosomes in the GnomAD database, including 10,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 993 hom., cov: 33)

Exomes 𝑓: 0.11 ( 9412 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -9.97

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=-0.78).

BP6

Variant 7-128837493-T-C is Benign according to our data. Variant chr7-128837493-T-C is described in ClinVar as [Benign]. Clinvar id is 129099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128837493-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-9.97 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 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.795T>C	p.Gly265=	synonymous_variant	4/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2 linkuse as main transcript	c.795T>C	p.Gly265=	synonymous_variant	4/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.795T>C	p.Gly265=	synonymous_variant	4/48	1	NM_001458.5	ENSP00000327145	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.795T>C	p.Gly265=	synonymous_variant	4/47	1		ENSP00000344002	A1	Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.110

AC:

16805

AN:

152164

Hom.:

994

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.0804

Gnomad AMR

AF:

0.0616

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.155

Gnomad FIN

AF:

0.0962

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.122

GnomAD3 exomes

AF:

0.105

AC:

26225

AN:

249778

Hom.:

1510

AF XY:

0.108

AC XY:

14585

AN XY:

135456

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.0471

Gnomad ASJ exome

AF:

0.111

Gnomad EAS exome

AF:

0.0944

Gnomad SAS exome

AF:

0.140

Gnomad FIN exome

AF:

0.101

Gnomad NFE exome

AF:

0.112

Gnomad OTH exome

AF:

0.114

GnomAD4 exome

AF:

0.112

AC:

163888

AN:

1461808

Hom.:

9412

Cov.:

AF XY:

0.113

AC XY:

82280

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.123

Gnomad4 AMR exome

AF:

0.0518

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.116

Gnomad4 SAS exome

AF:

0.141

Gnomad4 FIN exome

AF:

0.103

Gnomad4 NFE exome

AF:

0.112

Gnomad4 OTH exome

AF:

0.113

GnomAD4 genome

AF:

0.111

AC:

16830

AN:

152282

Hom.:

993

Cov.:

AF XY:

0.109

AC XY:

8152

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.122

Gnomad4 AMR

AF:

0.0615

Gnomad4 ASJ

AF:

0.118

Gnomad4 EAS

AF:

0.111

Gnomad4 SAS

AF:

0.154

Gnomad4 FIN

AF:

0.0962

Gnomad4 NFE

AF:

0.114

Gnomad4 OTH

AF:

0.125

Alfa

AF:

0.111

Hom.:

1154

Bravo

AF:

0.107

Asia WGS

AF:

0.151

AC:

525

AN:

3478

EpiCase

AF:

0.118

EpiControl

AF:

0.111

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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	Jan 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Gly265Gly in exon 4 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 12.1% (529/4356) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2291561). -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -

not provided

Benign:2

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

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 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

-0.78

CADD

Benign

0.46

DANN

Benign

0.65

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