rs12536635

chr7-128841258-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001458.5(FLNC):c.1902G>A(p.Glu634=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00611 in 1,614,090 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (43 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.11

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=-0.51).
• BP6: Variant 7-128841258-G-A is Benign according to our data. Variant chr7-128841258-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 194038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128841258-G-A is described in Lovd as [Benign]. Variant chr7-128841258-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00403 (613/152276) while in subpopulation NFE AF= 0.00684 (465/68000). AF 95% confidence interval is 0.00632. There are 4 homozygotes in gnomad4. There are 264 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 614 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.1902G>A	p.Glu634=	synonymous_variant	12/48	ENST00000325888.13
FLNC	NM_001127487.2	c.1902G>A	p.Glu634=	synonymous_variant	12/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.1902G>A	p.Glu634=	synonymous_variant	12/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.1902G>A	p.Glu634=	synonymous_variant	12/47	1		A1

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 614 AN: 152158 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00682

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00430 AC: 1073 AN: 249578 Hom.: 2 AF XY: 0.00434 AC XY: 588 AN XY: 135374

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.00745

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.000882

Gnomad NFE exome AF: 0.00666

Gnomad OTH exome AF: 0.00577

GnomAD4 exome AF: 0.00632 AC: 9245 AN: 1461814 Hom.: 43 Cov.: 33 AF XY: 0.00612 AC XY: 4448 AN XY: 727210

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00425

Gnomad4 ASJ exome AF: 0.00746

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.00745

Gnomad4 OTH exome AF: 0.00527

GnomAD4 genome AF: 0.00403 AC: 613 AN: 152276 Hom.: 4 Cov.: 33 AF XY: 0.00355 AC XY: 264 AN XY: 74462

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00684

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00598 Hom.: 2

Bravo AF: 0.00440

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2014	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	FLNC: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 24, 2018	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 16, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2019

This alteration is classified as likely 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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	9.6
Dann	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs12536635; hg19: chr7-128481312; COSMIC: COSV57960934; COSMIC: COSV57960934;