rs185746835

Variant summary

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

The NM_001458.5(FLNC):c.4097A>G(p.Asn1366Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000528 in 1,604,434 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 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 1 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 4.49

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 where missense usually causes diseases, FLNC

BP4

Computational evidence support a benign effect (MetaRNN=0.31522495).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000556 (808/1452148) while in subpopulation NFE AF= 0.000679 (755/1111946). AF 95% confidence interval is 0.000638. There are 1 homozygotes in gnomad4_exome. There are 394 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.4097A>G	p.Asn1366Ser	missense_variant	23/48	ENST00000325888.13
FLNC	NM_001127487.2 linkuse as main transcript	c.4097A>G	p.Asn1366Ser	missense_variant	23/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.4097A>G	p.Asn1366Ser	missense_variant	23/48	1	NM_001458.5	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.4097A>G	p.Asn1366Ser	missense_variant	23/47	1		A1	Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000165

AC:

AN:

242006

Hom.:

AF XY:

0.000114

AC XY:

AN XY:

131996

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000311

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000556

AC:

808

AN:

1452148

Hom.:

Cov.:

AF XY:

0.000545

AC XY:

394

AN XY:

722836

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000679

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.000256

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000334

Hom.:

Bravo

AF:

0.000268

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000483

AC:

ESP6500EA

AF:

0.000359

AC:

ExAC

AF:

0.000182

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 14, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2023	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	- -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with FLNC-related disease. Loss of function variants have been reported to cause myofibrillar myopathy, 5 (MIM#609524), distal myopathy, 4 (MIM#614065), familial hypertrophic cardiomyopathy, 26 (MIM#617047) and dilated cardiomyopathy (PMID: 32112656). Gain of function variants have also been reported to cause distal myopathy, 4 (MIM#614065) (PMID: 28008423, PMID: 23109048). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (44 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated filamin 12 repeat (NCBI, Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been previously reported as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The p.N1366S variant (also known as c.4097A>G), located in coding exon 23 of the FLNC gene, results from an A to G substitution at nucleotide position 4097. The asparagine at codon 1366 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in a pediatric cardiomyopathy cohort (Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.26

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.32

T;T

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.0

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.55

Sift

Benign

0.072

T;T

Sift4G

Benign

0.082

T;T

Polyphen

0.57

P;D

Vest4

0.49

MVP

0.83

MPC

0.48

ClinPred

0.24

GERP RS

5.1

Varity_R

0.22

gMVP

0.25

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