chr7-128840914-T-C

Position:

chr7-128840914-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BS1_SupportingBS2

The NM_001458.5(FLNC):c.1757T>C(p.Val586Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,610,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 6.27

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 Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNC. . Gene score misZ 2.789 (greater than the threshold 3.09). Trascript score misZ 5.9457 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, heart conduction disease, familial isolated restrictive cardiomyopathy, hypertrophic cardiomyopathy 26, distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5.

BP4

Computational evidence support a benign effect (MetaRNN=0.32348818).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000219 (33/150964) while in subpopulation AFR AF= 0.000758 (31/40888). AF 95% confidence interval is 0.000549. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.1757T>C	p.Val586Ala	missense_variant	11/48	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 linkuse as main transcript	c.1757T>C	p.Val586Ala	missense_variant	11/47		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.1757T>C	p.Val586Ala	missense_variant	11/48	1	NM_001458.5	ENSP00000327145.8		Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.1757T>C	p.Val586Ala	missense_variant	11/47	1		ENSP00000344002.6		Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.000219

AC:

AN:

150964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000758

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000485

GnomAD3 exomes

AF:

0.0000331

AC:

AN:

241768

Hom.:

AF XY:

0.0000303

AC XY:

AN XY:

131890

show subpopulations

Gnomad AFR exome

AF:

0.000407

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1459618

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725992

show subpopulations

Gnomad4 AFR exome

AF:

0.000718

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.000219

AC:

AN:

150964

Hom.:

Cov.:

AF XY:

0.000244

AC XY:

AN XY:

73670

show subpopulations

Gnomad4 AFR

AF:

0.000758

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000485

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.000219

ESP6500AA

AF:

0.000500

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 29, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2021

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 471987; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2023

The p.V586A variant (also known as c.1757T>C), located in coding exon 11 of the FLNC gene, results from a T to C substitution at nucleotide position 1757. The valine at codon 586 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort (Begay RL et al. JACC Clin Electrophysiol, 2018 Apr;4:504-514). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.32

T;T

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

1.3

L;L

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.017

D;D

Sift4G

Benign

0.11

T;T

Polyphen

0.72

P;D

Vest4

0.45

MVP

0.80

MPC

1.1

ClinPred

0.47

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.76

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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