rs181134489

chr7-128840175-C-Achr7-128840175-C-T

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.1549+15C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 1,613,320 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (42 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.246

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-128840175-C-A is Benign according to our data. Variant chr7-128840175-C-A is described in ClinVar as [Benign]. Clinvar id is 258126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128840175-C-A is described in Lovd as [Benign]. Variant chr7-128840175-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00392 (597/152256) while in subpopulation NFE AF= 0.0067 (456/68010). AF 95% confidence interval is 0.0062. There are 4 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 597 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.1549+15C>A		intron_variant		ENST00000325888.13
FLNC	NM_001127487.2	c.1549+15C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.1549+15C>A		intron_variant		1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.1549+15C>A		intron_variant		1		A1

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 597 AN: 152138 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00669

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00424 AC: 1053 AN: 248388 Hom.: 2 AF XY: 0.00428 AC XY: 577 AN XY: 134874

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00446

Gnomad ASJ exome AF: 0.00747

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000556

Gnomad FIN exome AF: 0.000907

Gnomad NFE exome AF: 0.00652

Gnomad OTH exome AF: 0.00579

GnomAD4 exome AF: 0.00624 AC: 9111 AN: 1461064 Hom.: 42 Cov.: 32 AF XY: 0.00604 AC XY: 4388 AN XY: 726798

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00427

Gnomad4 ASJ exome AF: 0.00742

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.00734

Gnomad4 OTH exome AF: 0.00522

GnomAD4 genome AF: 0.00392 AC: 597 AN: 152256 Hom.: 4 Cov.: 33 AF XY: 0.00344 AC XY: 256 AN XY: 74444

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00670

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00533 Hom.: 1

Bravo AF: 0.00433

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
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	- -

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	-0.80
Cadd	Benign	16
Dann	Benign	0.50

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: rs181134489; hg19: chr7-128480229; COSMIC: COSV57957045; COSMIC: COSV57957045;