rs149641783

Positions:

chr7-128846358-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001458.5(FLNC):c.4022G>A(p.Arg1341Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000827 in 1,613,308 control chromosomes in the GnomAD database, including 3 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 0.00075 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00084 ( 3 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 8.13

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016079754).

BP6

Variant 7-128846358-G-A is Benign according to our data. Variant chr7-128846358-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195741.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=3}. Variant chr7-128846358-G-A is described in Lovd as [Benign]. Variant chr7-128846358-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000749 (114/152288) while in subpopulation NFE AF= 0.000912 (62/68008). AF 95% confidence interval is 0.000729. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5 link	c.4022G>A	p.Arg1341Gln	missense_variant	23/48	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 link	c.4022G>A	p.Arg1341Gln	missense_variant	23/47		NP_001120959.1	Q14315-2Q59H94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 link	c.4022G>A	p.Arg1341Gln	missense_variant	23/48	1	NM_001458.5	ENSP00000327145.8		Q14315-1
FLNC	ENST00000346177.6 link	c.4022G>A	p.Arg1341Gln	missense_variant	23/47	1		ENSP00000344002.6		Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000912

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00105

AC:

260

AN:

248756

Hom.:

AF XY:

0.00117

AC XY:

158

AN XY:

135090

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00755

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000946

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.000836

AC:

1221

AN:

1461020

Hom.:

Cov.:

AF XY:

0.000923

AC XY:

671

AN XY:

726844

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00777

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000639

Gnomad4 OTH exome

AF:

0.00202

GnomAD4 genome

AF:

0.000749

AC:

114

AN:

152288

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000912

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.000842

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00178

AC:

ExAC

AF:

0.000933

AC:

113

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	FLNC: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 04, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2023	Variant summary: FLNC c.4022G>A (p.Arg1341Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 248756 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 133.79 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.4022G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy, without strong evidence for causality. 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, 25208129). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as VUS whle five classified the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 20, 2021

- -

FLNC-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

T;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.016

T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.99

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.57

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.17

B;D

Vest4

0.73

MVP

0.71

MPC

0.96

ClinPred

0.052

GERP RS

5.1

Varity_R

0.19

gMVP

0.50

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