rs199804244

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP6BS1BS2

The NM_001458.5(FLNC):c.3938G>A(p.Arg1313Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,613,908 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1313G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 2.03

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant where missense usually causes diseases, FLNC

BP6

Variant 7-128846137-G-A is Benign according to our data. Variant chr7-128846137-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472052.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}. Variant chr7-128846137-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000362 (55/152132) while in subpopulation AMR AF= 0.00111 (17/15286). AF 95% confidence interval is 0.000708. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.3938G>A	p.Arg1313Gln	missense_variant	22/48	ENST00000325888.13
FLNC	NM_001127487.2 linkuse as main transcript	c.3938G>A	p.Arg1313Gln	missense_variant	22/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.3938G>A	p.Arg1313Gln	missense_variant	22/48	1	NM_001458.5	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.3938G>A	p.Arg1313Gln	missense_variant	22/47	1		A1	Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

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:

0.000529

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000205

AC:

AN:

249112

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

135262

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.0000580

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:

0.000398

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000414

AC:

605

AN:

1461776

Hom.:

Cov.:

AF XY:

0.000419

AC XY:

305

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000523

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000362

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000319

Hom.:

Bravo

AF:

0.000348

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

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

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

FLNC NM_001458.4 exon 22 p.Arg1313Gln (c.3938G>A): This variant has not been reported in the literature and is present in 0.04% (51/128340) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/7-128486191-G-A). This variant is present in ClinVar (Variation ID:472052). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2024

The p.R1313Q variant (also known as c.3938G>A), located in coding exon 22 of the FLNC gene, results from a G to A substitution at nucleotide position 3938. The arginine at codon 1313 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in a congenital heart disease exome testing cohort; however, clinical details were limited (Watkins WS et al. Nat Commun, 2019 10;10:4722). 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

GeneDx

Mar 07, 2018

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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

FLNC: BP4, BS2 -

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 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.053

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.076

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

0.63

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.39

N;N

REVEL

Uncertain

0.41

Sift

Benign

0.81

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.016

B;P

Vest4

0.56

MVP

0.70

MPC

0.64

ClinPred

0.033

GERP RS

5.1

Varity_R

0.041

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.22

Position offset: 1

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