rs12530507

Positions:

• chr7-128852771-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.6004+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,613,312 control chromosomes in the GnomAD database, including 283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 33)
  • Exomes 𝑓: 0.017 (266 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.159

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-128852771-G-A is Benign according to our data. Variant chr7-128852771-G-A is described in ClinVar as [Benign]. Clinvar id is 258152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128852771-G-A is described in Lovd as [Likely_benign]. Variant chr7-128852771-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0118 (1798/152318) while in subpopulation NFE AF= 0.0189 (1286/68026). AF 95% confidence interval is 0.018. There are 17 homozygotes in gnomad4. There are 834 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1798 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.6004+19G>A		intron_variant		ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.5905+19G>A		intron_variant			NP_001120959.1
FLNC-AS1	NR_149055.1	n.215+514C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.6004+19G>A		intron_variant		1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.5905+19G>A		intron_variant		1		ENSP00000344002.6
FLNC-AS1	ENST00000469965.1	n.215+514C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1798 AN: 152200 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0118 AC: 2933 AN: 248958 Hom.: 31 AF XY: 0.0116 AC XY: 1569 AN XY: 135188

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.00893

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0171 AC: 25051 AN: 1460994 Hom.: 266 Cov.: 33 AF XY: 0.0164 AC XY: 11893 AN XY: 726780

Gnomad4 AFR exome AF: 0.00308

Gnomad4 AMR exome AF: 0.00917

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.0171

Gnomad4 NFE exome AF: 0.0204

Gnomad4 OTH exome AF: 0.0133

GnomAD4 genome AF: 0.0118 AC: 1798 AN: 152318 Hom.: 17 Cov.: 33 AF XY: 0.0112 AC XY: 834 AN XY: 74482

Gnomad4 AFR AF: 0.00431

Gnomad4 AMR AF: 0.00981

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0152

Gnomad4 NFE AF: 0.0189

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.0127 Hom.: 3

Bravo AF: 0.0114

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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 02, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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 29, 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.47

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: rs12530507; hg19: chr7-128492825; COSMIC: COSV57949883;