7-128842386-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001458.5(FLNC):c.2265+12C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0865 in 1,613,054 control chromosomes in the GnomAD database, including 12,991 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4050 hom., cov: 33)
  • Exomes 𝑓: 0.078 (8941 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.07

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=-0.74).
• BP6: Variant 7-128842386-C-G is Benign according to our data. Variant chr7-128842386-C-G is described in ClinVar as [Benign]. Clinvar id is 226640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128842386-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.2265+12C>G		intron_variant		ENST00000325888.13
FLNC	NM_001127487.2	c.2265+12C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.2265+12C>G		intron_variant		1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.2265+12C>G		intron_variant		1		A1
FLNC	ENST00000388853.3	n.381+12C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25633 AN: 152046 Hom.: 4037 Cov.: 33

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0351

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0532

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.126 AC: 31075 AN: 247176 Hom.: 3672 AF XY: 0.118 AC XY: 15945 AN XY: 134576

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.362

Gnomad SAS exome AF: 0.170

Gnomad FIN exome AF: 0.0406

Gnomad NFE exome AF: 0.0536

Gnomad OTH exome AF: 0.0939

GnomAD4 exome AF: 0.0779 AC: 113798 AN: 1460890 Hom.: 8941 Cov.: 34 AF XY: 0.0789 AC XY: 57341 AN XY: 726772

Gnomad4 AFR exome AF: 0.406

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.334

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.0413

Gnomad4 NFE exome AF: 0.0511

Gnomad4 OTH exome AF: 0.0952

GnomAD4 genome AF: 0.169 AC: 25676 AN: 152164 Hom.: 4050 Cov.: 33 AF XY: 0.167 AC XY: 12453 AN XY: 74404

Gnomad4 AFR AF: 0.404

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.350

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.0351

Gnomad4 NFE AF: 0.0532

Gnomad4 OTH AF: 0.130

Alfa AF: 0.0346 Hom.: 55

Bravo AF: 0.185

ClinVar

Significance: Benign

Submissions summary: Benign:7

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	Jul 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	2265+12C>G in intron 14 of FLNC: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence. It has been identified in 36.7% (1523/4152) of African American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs2291566). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	GeneDx	Feb 12, 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	Clinical Genetics, Academic Medical Center	-	- -

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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.92
Dann	Benign	0.73

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: rs2291566; hg19: chr7-128482440; COSMIC: COSV57955087;