rs117653869

Positions:

• chr7-128852763-G-A
• chr7-128852763-G-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.6004+11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0093 in 1,613,252 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0095 (72 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0660

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=-0.85).
• BP6: Variant 7-128852763-G-A is Benign according to our data. Variant chr7-128852763-G-A is described in ClinVar as [Benign]. Clinvar id is 258151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128852763-G-A is described in Lovd as [Benign]. Variant chr7-128852763-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00705 (1074/152248) while in subpopulation NFE AF= 0.0112 (759/67986). AF 95% confidence interval is 0.0105. There are 7 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1074 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.6004+11G>A		intron_variant		ENST00000325888.13	NP_001449.3
FLNC-AS1	NR_149055.1	n.215+522C>T		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.5905+11G>A		intron_variant			NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.6004+11G>A		intron_variant		1	NM_001458.5	ENSP00000327145	P3
FLNC	ENST00000346177.6	c.5905+11G>A		intron_variant		1		ENSP00000344002	A1
FLNC-AS1	ENST00000469965.1	n.215+522C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00707 AC: 1075 AN: 152130 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00981

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00717 AC: 1786 AN: 249034 Hom.: 12 AF XY: 0.00710 AC XY: 960 AN XY: 135226

Gnomad AFR exome AF: 0.00233

Gnomad AMR exome AF: 0.00690

Gnomad ASJ exome AF: 0.00389

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.00469

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00844

GnomAD4 exome AF: 0.00953 AC: 13923 AN: 1461004 Hom.: 72 Cov.: 33 AF XY: 0.00925 AC XY: 6720 AN XY: 726774

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00698

Gnomad4 ASJ exome AF: 0.00413

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.00464

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.00820

GnomAD4 genome AF: 0.00705 AC: 1074 AN: 152248 Hom.: 7 Cov.: 33 AF XY: 0.00647 AC XY: 482 AN XY: 74460

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.00980

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00645 Hom.: 2

Bravo AF: 0.00739

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Apr 04, 2023	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FLNC: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
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)	-	- -

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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.55
DANN	Benign	0.57

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: rs117653869; hg19: chr7-128492817;