chr7-128840085-A-G

Position:

chr7-128840085-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001458.5(FLNC):c.1474A>G(p.Lys492Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000417 in 1,614,154 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 1 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 3.80

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 -10 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=0.25621033).

BP6

Variant 7-128840085-A-G is Benign according to our data. Variant chr7-128840085-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 471978.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}. Variant chr7-128840085-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000432 (631/1461792) while in subpopulation NFE AF= 0.000523 (582/1112008). AF 95% confidence interval is 0.000488. There are 1 homozygotes in gnomad4_exome. There are 311 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.1474A>G	p.Lys492Glu	missense_variant	9/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2 linkuse as main transcript	c.1474A>G	p.Lys492Glu	missense_variant	9/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.1474A>G	p.Lys492Glu	missense_variant	9/48	1	NM_001458.5	ENSP00000327145	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.1474A>G	p.Lys492Glu	missense_variant	9/47	1		ENSP00000344002	A1	Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000273

AC:

AN:

249444

Hom.:

AF XY:

0.000303

AC XY:

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000503

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000432

AC:

631

AN:

1461792

Hom.:

Cov.:

AF XY:

0.000428

AC XY:

311

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000523

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000276

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000326

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000240

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 16, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	FLNC: BS1 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2023

The p.K492E variant (also known as c.1474A>G), located in coding exon 9 of the FLNC gene, results from an A to G substitution at nucleotide position 1474. The lysine at codon 492 is replaced by glutamic acid, an amino acid with similar properties. This variant has been detected in patients from hypertrophic and dilated cardiomyopathy cohorts with limited detail, and in cohorts not selected for cardiovascular diagnoses including in a Rett syndrome cohort and a frontotemporal dementia cohort (Janssens J et al. Acta Neuropathol Commun. 2015 Nov;3:68; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Sajan SA et al. Genet. Med., 2017 01;19:13-19; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 07, 2024

Variant summary: FLNC c.1474A>G (p.Lys492Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 249444 control chromosomes. The observed variant frequency is approximately 35 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Dilated Cardiomyopathy phenotype (7.8e-06), strongly suggesting that the variant is benign. c.1474A>G has been reported in the literature in patients from hypertrophic and dilated cardiomyopathy cohorts with limited detail (example: Gomez_2017 and van Lint_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28356264, 30847666). ClinVar contains an entry for this variant (Variation ID: 471978). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Sep 21, 2021

- -

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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.26

T;T

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.8

D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.046

D;D

Polyphen

0.54

P;D

Vest4

0.58

MVP

0.81

MPC

0.65

ClinPred

0.13

GERP RS

5.3

Varity_R

0.52

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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