rs372251350

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001458.5(FLNC):c.6817G>A(p.Ala2273Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,605,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 2.63

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06056899).

BP6

Variant 7-128854502-G-A is Benign according to our data. Variant chr7-128854502-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 425427.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr7-128854502-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5 link	c.6817G>A	p.Ala2273Thr	missense_variant	Exon 41 of 48	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 link	c.6718G>A	p.Ala2240Thr	missense_variant	Exon 40 of 47		NP_001120959.1	Q14315-2Q59H94
FLNC-AS1	NR_149055.1 link	n.103-1105C>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FLNC	ENST00000325888.13 link	c.6817G>A	p.Ala2273Thr	missense_variant	Exon 41 of 48	1	NM_001458.5	ENSP00000327145.8	Q14315-1
FLNC	ENST00000346177.6 link	c.6718G>A	p.Ala2240Thr	missense_variant	Exon 40 of 47	1		ENSP00000344002.6	Q14315-2
FLNC-AS1	ENST00000469965.1 link	n.103-1105C>T		intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.0000722

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

228146

Hom.:

AF XY:

0.000145

AC XY:

AN XY:

124188

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000622

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000605

Gnomad SAS exome

AF:

0.000349

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000156

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

179

AN:

1452816

Hom.:

Cov.:

AF XY:

0.000137

AC XY:

AN XY:

721926

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000464

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.000413

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.0000999

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000263

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.0000991

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Dec 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FLNC c.6817G>A; p.Ala2273Thr variant (rs372251350), to our knowledge, is not reported in the medical literature associated with disease but is reported in ClinVar (Variation ID: 425427). This variant is found in the general population with an overall allele frequency of 0.013% (29/228146 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.201). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FLNC: BP4 -

Jan 24, 2020

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Distal myopathy with posterior leg and anterior hand involvement

Uncertain:1

Jun 21, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Sep 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A2273T variant (also known as c.6817G>A), located in coding exon 41 of the FLNC gene, results from a G to A substitution at nucleotide position 6817. The alanine at codon 2273 is replaced by threonine, an amino acid with similar properties. This alteration was reported in a control cohort (Janssens J et al. Acta Neuropathol Commun, 2015 Nov;3:68). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Jan 17, 2025

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.6817G>A (p.Ala2273Thr) results in a non-conservative amino acid change located in the Filamin-type immunoglobulin domain (IPR001298) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 228146 control chromosomes. The observed variant frequency is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Dilated Cardiomyopathy phenotype (7.8e-06). To our knowledge, no occurrence of c.6817G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 425427). 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 27, 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

0.061

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.061

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-1.7

N;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

1.0

N;N

REVEL

Benign

0.20

Sift

Benign

0.54

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0060

B;B

Vest4

0.037

MVP

0.30

MPC

0.68

ClinPred

0.041

GERP RS

5.0

Varity_R

0.037

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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