rs201149834

Positions:

• chr7-128857346-A-G

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.7780+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,599,408 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.69

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=-0.91).
• BP6: Variant 7-128857346-A-G is Benign according to our data. Variant chr7-128857346-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128857346-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.004 (608/152056) while in subpopulation AFR AF= 0.0102 (422/41418). AF 95% confidence interval is 0.00939. There are 1 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 608 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.7780+10A>G		intron_variant		ENST00000325888.13
FLNC-AS1	NR_149055.1	n.103-3949T>C		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.7681+10A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.7780+10A>G		intron_variant		1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.7681+10A>G		intron_variant		1		A1
FLNC-AS1	ENST00000469965.1	n.103-3949T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 607 AN: 151938 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00281 AC: 685 AN: 243776 Hom.: 1 AF XY: 0.00240 AC XY: 319 AN XY: 132712

Gnomad AFR exome AF: 0.00969

Gnomad AMR exome AF: 0.00624

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00213

Gnomad SAS exome AF: 0.000821

Gnomad FIN exome AF: 0.00114

Gnomad NFE exome AF: 0.00203

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00184 AC: 2656 AN: 1447352 Hom.: 4 Cov.: 31 AF XY: 0.00170 AC XY: 1228 AN XY: 720652

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.00549

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00661

Gnomad4 SAS exome AF: 0.000732

Gnomad4 FIN exome AF: 0.00117

Gnomad4 NFE exome AF: 0.00138

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00400 AC: 608 AN: 152056 Hom.: 1 Cov.: 33 AF XY: 0.00378 AC XY: 281 AN XY: 74342

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00249 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Aug 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2017	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	PreventionGenetics, part of Exact Sciences	-	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 31, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

FLNC: BS1 -

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	-0.91
CADD	Benign	0.17
DANN	Benign	0.45

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: rs201149834; hg19: chr7-128497400;