rs768941858

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5BP4BP6BS2

The NM_001458.5(FLNC):c.7123G>A(p.Val2375Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,910 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. V2375L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.88

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:

FLNC-AS1 (HGNC:53474): (FLNC antisense RNA 1)

FLNC-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-128854900-G-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.40396622).

BP6

Variant 7-128854900-G-A is Benign according to our data. Variant chr7-128854900-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 571045.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5 link	c.7123G>A	p.Val2375Ile	missense_variant	Exon 42 of 48	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 link	c.7024G>A	p.Val2342Ile	missense_variant	Exon 41 of 47		NP_001120959.1	Q14315-2Q59H94
FLNC-AS1	NR_149055.1 link	n.103-1503C>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FLNC	ENST00000325888.13 link	c.7123G>A	p.Val2375Ile	missense_variant	Exon 42 of 48	1	NM_001458.5	ENSP00000327145.8	Q14315-1
FLNC	ENST00000346177.6 link	c.7024G>A	p.Val2342Ile	missense_variant	Exon 41 of 47	1		ENSP00000344002.6	Q14315-2
FLNC-AS1	ENST00000469965.1 link	n.103-1503C>T		intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000401

AC:

AN:

249434

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135346

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461734

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000580

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 10, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in an adult patient with myofibrillar myopathy (MFM) and lower motor neuron (LMN) syndrome (Chen et al., 2019); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 571045; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31421687) -

Nov 10, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Apr 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V2375I variant (also known as c.7123G>A), located in coding exon 42 of the FLNC gene, results from a G to A substitution at nucleotide position 7123. The valine at codon 2375 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in an individual with features of myofibrillar myopathy (Chen J et al. BMC Neurol, 2019 Aug;19:198). An alternate amino acid substitution at this codon, p.V2375F, was reported in one individual with hypertrophic cardiomyopathy; however clinical details were limited (Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10:[Epub ahead of print]). This amino acid position is highly 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

Nov 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FLNC c.7123G>A (p.Val2375Ile) results in a conservative amino acid change located in the Filamin/ABP280 repeat profile (IPR017868) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 249434 control chromosomes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Cardiomyopathy phenotype (1.1e-05). c.7123G>A has been reported in the literature in individuals affected with Cardiomyopathy (Chen_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31421687). ClinVar contains an entry for this variant (Variation ID: 571045). Based on the evidence outlined above, the variant was classified as likely benign. -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant

Benign:1

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.40

T;T

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

3.3

M;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.91

N;N

REVEL

Uncertain

0.55

Sift

Benign

0.16

T;T

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.78

P;D

Vest4

0.44

MVP

0.78

MPC

1.5

ClinPred

0.41

GERP RS

5.2

Varity_R

0.19

gMVP

0.39

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