7-128846392-C-T

Variant names:

• chr7-128846392-C-T
• rs75770585
• NM_001458.5:c.4056C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001458.5(FLNC):​c.4056C>T​(p.Arg1352Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0565 in 1,611,006 control chromosomes in the GnomAD database, including 5,177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (1043 hom., cov: 33)
  • Exomes 𝑓: 0.053 (4134 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -8.61

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-128846392-C-T is Benign according to our data. Variant chr7-128846392-C-T is described in ClinVar as [Benign]. Clinvar id is 129089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128846392-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-8.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.4056C>T	p.Arg1352Arg	synonymous_variant	Exon 23 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.4056C>T	p.Arg1352Arg	synonymous_variant	Exon 23 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.4056C>T	p.Arg1352Arg	synonymous_variant	Exon 23 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.4056C>T	p.Arg1352Arg	synonymous_variant	Exon 23 of 47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes AF: 0.0895 AC: 13616 AN: 152072 Hom.: 1038 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0897

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.0939

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0385

Gnomad OTH AF: 0.0766

GnomAD3 exomes AF: 0.0888 AC: 21928 AN: 247042 Hom.: 1885 AF XY: 0.0827 AC XY: 11114 AN XY: 134336

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.328

Gnomad SAS exome AF: 0.0849

Gnomad FIN exome AF: 0.0264

Gnomad NFE exome AF: 0.0406

Gnomad OTH exome AF: 0.0707

GnomAD4 exome AF: 0.0531 AC: 77424 AN: 1458816 Hom.: 4134 Cov.: 34 AF XY: 0.0532 AC XY: 38649 AN XY: 725858

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.0181

Gnomad4 EAS exome AF: 0.293

Gnomad4 SAS exome AF: 0.0844

Gnomad4 FIN exome AF: 0.0273

Gnomad4 NFE exome AF: 0.0364

Gnomad4 OTH exome AF: 0.0608

GnomAD4 genome AF: 0.0896 AC: 13632 AN: 152190 Hom.: 1043 Cov.: 33 AF XY: 0.0901 AC XY: 6708 AN XY: 74416

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.0894

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.311

Gnomad4 SAS AF: 0.0936

Gnomad4 FIN AF: 0.0209

Gnomad4 NFE AF: 0.0385

Gnomad4 OTH AF: 0.0762

Alfa AF: 0.0559 Hom.: 212

Bravo AF: 0.102

Asia WGS AF: 0.173 AC: 601 AN: 3478

EpiCase AF: 0.0359

EpiControl AF: 0.0395

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Feb 12, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg1352Arg in exon 23 of FLNC: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 15.9% (661/4150) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs75770585). -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 10, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 13, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 24, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.032
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Other links and lift over

dbSNP: rs75770585; hg19: chr7-128486446; COSMIC: COSV57959725; COSMIC: COSV57959725;