rs58914363

chr7-128851552-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):c.5766G>A(p.Ala1922=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,613,974 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1922A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00083 (4 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -5.04

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-128851552-G-A is Benign according to our data. Variant chr7-128851552-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128851552-G-A is described in Lovd as [Benign]. Variant chr7-128851552-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00102 (155/152328) while in subpopulation AMR AF= 0.00209 (32/15306). AF 95% confidence interval is 0.00152. There are 1 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 155 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.5766G>A	p.Ala1922=	synonymous_variant	35/48	ENST00000325888.13
FLNC-AS1	NR_149055.1	n.216-52C>T		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.5667G>A	p.Ala1889=	synonymous_variant	34/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.5766G>A	p.Ala1922=	synonymous_variant	35/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.5667G>A	p.Ala1889=	synonymous_variant	34/47	1		A1
FLNC-AS1	ENST00000469965.1	n.216-52C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152210 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000908 AC: 228 AN: 251000 Hom.: 1 AF XY: 0.000943 AC XY: 128 AN XY: 135782

Gnomad AFR exome AF: 0.000747

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000879

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000832 AC: 1216 AN: 1461646 Hom.: 4 Cov.: 34 AF XY: 0.000866 AC XY: 630 AN XY: 727130

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.000997

Gnomad4 NFE exome AF: 0.000818

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.000980 AC XY: 73 AN XY: 74488

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000980 Hom.: 0

Bravo AF: 0.00122

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2024	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FLNC: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

Apr 16, 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.025
Dann	Benign	0.71

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: rs58914363; hg19: chr7-128491606; COSMIC: COSV100368942;