chr7-128845186-C-T

Position:

chr7-128845186-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001458.5(FLNC):c.3721C>T(p.Arg1241Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00865 in 1,613,962 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1241H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0069 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0088 ( 67 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.819

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 -19 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=0.0095562935).

BP6

Variant 7-128845186-C-T is Benign according to our data. Variant chr7-128845186-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128845186-C-T is described in Lovd as [Benign]. Variant chr7-128845186-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00693 (1055/152346) while in subpopulation NFE AF= 0.0111 (752/68038). AF 95% confidence interval is 0.0104. There are 11 homozygotes in gnomad4. There are 544 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1055 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.3721C>T	p.Arg1241Cys	missense_variant	21/48	ENST00000325888.13
FLNC	NM_001127487.2 linkuse as main transcript	c.3721C>T	p.Arg1241Cys	missense_variant	21/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.3721C>T	p.Arg1241Cys	missense_variant	21/48	1	NM_001458.5	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.3721C>T	p.Arg1241Cys	missense_variant	21/47	1		A1	Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.00694

AC:

1056

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00137

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0133

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0111

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00597

AC:

1479

AN:

247646

Hom.:

AF XY:

0.00619

AC XY:

833

AN XY:

134574

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00229

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.00942

Gnomad OTH exome

AF:

0.00512

GnomAD4 exome

AF:

0.00883

AC:

12901

AN:

1461616

Hom.:

Cov.:

AF XY:

0.00865

AC XY:

6290

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00119

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.00218

Gnomad4 FIN exome

AF:

0.0114

Gnomad4 NFE exome

AF:

0.0104

Gnomad4 OTH exome

AF:

0.00662

GnomAD4 genome

AF:

0.00693

AC:

1055

AN:

152346

Hom.:

Cov.:

AF XY:

0.00730

AC XY:

544

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0133

Gnomad4 NFE

AF:

0.0111

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00851

Hom.:

Bravo

AF:

0.00589

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00115

AC:

ESP6500EA

AF:

0.00951

AC:

ExAC

AF:

0.00624

AC:

756

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00943

EpiControl

AF:

0.00741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2015	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FLNC: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 16, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2018

This alteration is classified as 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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

D;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.0096

T;T

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.56

Sift

Benign

0.037

D;D

Sift4G

Benign

0.061

T;T

Polyphen

0.10

B;D

Vest4

0.60

MVP

0.66

MPC

1.1

ClinPred

0.019

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.18

gMVP

0.59

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