7-128855284-C-T

Position:

• chr7-128855284-C-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.7221C>T​(p.Asp2407Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 1,612,590 control chromosomes in the GnomAD database, including 11,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (3624 hom., cov: 33)
  • Exomes 𝑓: 0.068 (7911 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -6.38

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

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 7-128855284-C-T is Benign according to our data. Variant chr7-128855284-C-T is described in ClinVar as [Benign]. Clinvar id is 129097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128855284-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.7221C>T	p.Asp2407Asp	synonymous_variant	43/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.7122C>T	p.Asp2374Asp	synonymous_variant	42/47		NP_001120959.1
FLNC-AS1	NR_149055.1	n.103-1887G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.7221C>T	p.Asp2407Asp	synonymous_variant	43/48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.7122C>T	p.Asp2374Asp	synonymous_variant	42/47	1		ENSP00000344002.6
FLNC-AS1	ENST00000469965.1	n.103-1887G>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23612 AN: 152032 Hom.: 3617 Cov.: 33

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0215

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0422

Gnomad OTH AF: 0.121

GnomAD3 exomes AF: 0.117 AC: 29283 AN: 249516 Hom.: 3466 AF XY: 0.111 AC XY: 15022 AN XY: 135372

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.361

Gnomad SAS exome AF: 0.170

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.0435

Gnomad OTH exome AF: 0.0872

GnomAD4 exome AF: 0.0677 AC: 98835 AN: 1460440 Hom.: 7911 Cov.: 31 AF XY: 0.0692 AC XY: 50255 AN XY: 726642

Gnomad4 AFR exome AF: 0.381

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.0181

Gnomad4 EAS exome AF: 0.333

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.0275

Gnomad4 NFE exome AF: 0.0398

Gnomad4 OTH exome AF: 0.0849

GnomAD4 genome AF: 0.155 AC: 23637 AN: 152150 Hom.: 3624 Cov.: 33 AF XY: 0.155 AC XY: 11499 AN XY: 74384

Gnomad4 AFR AF: 0.380

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.351

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.0215

Gnomad4 NFE AF: 0.0422

Gnomad4 OTH AF: 0.121

Alfa AF: 0.0604 Hom.: 1096

Bravo AF: 0.172

Asia WGS AF: 0.265 AC: 919 AN: 3478

EpiCase AF: 0.0396

EpiControl AF: 0.0434

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Asp2407Asp in exon 43 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 35.8% (1551/4334) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs3816885). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 13, 2017	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2018

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

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
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.17
DANN	Benign	0.82

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: rs3816885; hg19: chr7-128495338; COSMIC: COSV57957812;