rs536456072

chr7-128842691-G-Achr7-128842691-G-C

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.2382G>A(p.Ala794=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000983 in 1,556,234 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A794A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -8.08

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 7-128842691-G-A is Benign according to our data. Variant chr7-128842691-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 472007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128842691-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-8.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000985 (15/152296) while in subpopulation EAS AF= 0.00271 (14/5172). AF 95% confidence interval is 0.00164. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.2382G>A	p.Ala794=	synonymous_variant	15/48	ENST00000325888.13
FLNC	NM_001127487.2	c.2382G>A	p.Ala794=	synonymous_variant	15/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.2382G>A	p.Ala794=	synonymous_variant	15/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.2382G>A	p.Ala794=	synonymous_variant	15/47	1		A1
FLNC	ENST00000388853.3	n.498G>A		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000366 AC: 58 AN: 158620 Hom.: 0 AF XY: 0.000331 AC XY: 28 AN XY: 84634

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000400

Gnomad ASJ exome AF: 0.000352

Gnomad EAS exome AF: 0.00438

Gnomad SAS exome AF: 0.0000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.0000983 AC: 138 AN: 1403938 Hom.: 0 Cov.: 47 AF XY: 0.000102 AC XY: 71 AN XY: 692886

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000278

Gnomad4 ASJ exome AF: 0.000238

Gnomad4 EAS exome AF: 0.00259

Gnomad4 SAS exome AF: 0.000150

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000129

Gnomad4 OTH exome AF: 0.000172

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74462

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00271

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000166

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 29, 2018	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2020

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 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.086
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs536456072; hg19: chr7-128482745;