rs12536635

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001458.5(FLNC):c.1902G>A(p.Glu634Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00611 in 1,614,090 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0063 ( 43 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 2.11

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=-0.51).

BP6

Variant 7-128841258-G-A is Benign according to our data. Variant chr7-128841258-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 194038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128841258-G-A is described in Lovd as [Benign]. Variant chr7-128841258-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.11 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00403 (613/152276) while in subpopulation NFE AF= 0.00684 (465/68000). AF 95% confidence interval is 0.00632. There are 4 homozygotes in gnomad4. There are 264 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 613 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5 link	c.1902G>A	p.Glu634Glu	synonymous_variant	Exon 12 of 48	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 link	c.1902G>A	p.Glu634Glu	synonymous_variant	Exon 12 of 47		NP_001120959.1	Q14315-2Q59H94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FLNC	ENST00000325888.13 link	c.1902G>A	p.Glu634Glu	synonymous_variant	Exon 12 of 48	1	NM_001458.5	ENSP00000327145.8	Q14315-1
FLNC	ENST00000346177.6 link	c.1902G>A	p.Glu634Glu	synonymous_variant	Exon 12 of 47	1		ENSP00000344002.6	Q14315-2
FLNC	ENST00000388853.3 link	n.-73G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00404

AC:

614

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00682

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00430

AC:

1073

AN:

249578

Hom.:

AF XY:

0.00434

AC XY:

588

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.00440

Gnomad ASJ exome

AF:

0.00745

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.000882

Gnomad NFE exome

AF:

0.00666

Gnomad OTH exome

AF:

0.00577

GnomAD4 exome

AF:

0.00632

AC:

9245

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00612

AC XY:

4448

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.00425

Gnomad4 ASJ exome

AF:

0.00746

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000510

Gnomad4 FIN exome

AF:

0.00109

Gnomad4 NFE exome

AF:

0.00745

Gnomad4 OTH exome

AF:

0.00527

GnomAD4 genome

AF:

0.00403

AC:

613

AN:

152276

Hom.:

Cov.:

AF XY:

0.00355

AC XY:

264

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00684

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00598

Hom.:

Bravo

AF:

0.00440

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Nov 21, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

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

- -

Aug 19, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 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. -

Dec 01, 2023

Athena Diagnostics

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

- -

not provided

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FLNC: BP4, BS2 -

Cardiomyopathy

Benign:1

May 16, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 02, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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 03, 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

-0.51

CADD

Benign

9.6

DANN

Benign

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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