rs2291561

Variant names:

• chr7-128837493-T-C
• rs2291561
• NM_001458.5:c.795T>C

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.795T>C​(p.Gly265Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,614,090 control chromosomes in the GnomAD database, including 10,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (993 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9412 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -9.97

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=-0.78).
• BP6: Variant 7-128837493-T-C is Benign according to our data. Variant chr7-128837493-T-C is described in ClinVar as [Benign]. Clinvar id is 129099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128837493-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-9.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.795T>C	p.Gly265Gly	synonymous_variant	Exon 4 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.795T>C	p.Gly265Gly	synonymous_variant	Exon 4 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.795T>C	p.Gly265Gly	synonymous_variant	Exon 4 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.795T>C	p.Gly265Gly	synonymous_variant	Exon 4 of 47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16805 AN: 152164 Hom.: 994 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.0804

Gnomad AMR AF: 0.0616

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.0962

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.122

GnomAD3 exomes AF: 0.105 AC: 26225 AN: 249778 Hom.: 1510 AF XY: 0.108 AC XY: 14585 AN XY: 135456

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0471

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.0944

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.112 AC: 163888 AN: 1461808 Hom.: 9412 Cov.: 37 AF XY: 0.113 AC XY: 82280 AN XY: 727210

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.0518

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.111 AC: 16830 AN: 152282 Hom.: 993 Cov.: 33 AF XY: 0.109 AC XY: 8152 AN XY: 74454

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0615

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.0962

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.125

Alfa AF: 0.111 Hom.: 1154

Bravo AF: 0.107

Asia WGS AF: 0.151 AC: 525 AN: 3478

EpiCase AF: 0.118

EpiControl AF: 0.111

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 07, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 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. -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 04, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

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.Gly265Gly in exon 4 of FLNC: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 12.1% (529/4356) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2291561). -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 21, 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	-0.78
CADD	Benign	0.46
DANN	Benign	0.65

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: rs2291561; hg19: chr7-128477547; COSMIC: COSV57955939; COSMIC: COSV57955939;