rs199652368

Positions:

Variant summary

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

The NM_001458.5(FLNC):c.2507C>A(p.Pro836Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000422 in 1,614,048 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 6.04

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=0.015451163).

BP6

Variant 7-128842911-C-A is Benign according to our data. Variant chr7-128842911-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 387217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128842911-C-A is described in Lovd as [Benign]. Variant chr7-128842911-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00192 (293/152356) while in subpopulation AFR AF= 0.00584 (243/41578). AF 95% confidence interval is 0.00524. There are 1 homozygotes in gnomad4. There are 136 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 293 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.2507C>A	p.Pro836Gln	missense_variant	16/48	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 linkuse as main transcript	c.2507C>A	p.Pro836Gln	missense_variant	16/47		NP_001120959.1	Q14315-2Q59H94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.2507C>A	p.Pro836Gln	missense_variant	16/48	1	NM_001458.5	ENSP00000327145.8		Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.2507C>A	p.Pro836Gln	missense_variant	16/47	1		ENSP00000344002.6		Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

292

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00586

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000534

AC:

133

AN:

249110

Hom.:

AF XY:

0.000466

AC XY:

AN XY:

135318

show subpopulations

Gnomad AFR exome

AF:

0.00609

Gnomad AMR exome

AF:

0.000637

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:

0.0000886

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000265

AC:

388

AN:

1461692

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

177

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00624

Gnomad4 AMR exome

AF:

0.000648

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000998

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.00192

AC:

293

AN:

152356

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00584

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.00237

ESP6500AA

AF:

0.00540

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.000586

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2021	This variant is associated with the following publications: (PMID: 28356264) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 13, 2017

- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 20, 2023

- -

FLNC-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2021

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 11, 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

Likely 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

Uncertain

0.36

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

D;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.015

T;T

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-4.2

D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.010

D;D

Sift4G

Benign

0.15

T;T

Polyphen

1.0

D;D

Vest4

0.80

MVP

0.64

MPC

0.93

ClinPred

0.024

GERP RS

5.7

Varity_R

0.26

gMVP

0.51

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