rs79790270

Positions:

• chr7-128851443-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.5669-12C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,613,920 control chromosomes in the GnomAD database, including 1,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (93 hom., cov: 33)
  • Exomes 𝑓: 0.034 (1057 hom.)
• Consequence: FLNC NM_001458.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003501
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0410

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=-0.71).
• BP6: Variant 7-128851443-C-T is Benign according to our data. Variant chr7-128851443-C-T is described in ClinVar as [Benign]. Clinvar id is 258149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128851443-C-T is described in Lovd as [Benign]. Variant chr7-128851443-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0275 (4189/152324) while in subpopulation NFE AF= 0.0377 (2567/68028). AF 95% confidence interval is 0.0365. There are 93 homozygotes in gnomad4. There are 2170 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4189 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.5669-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000325888.13
FLNC-AS1	NR_149055.1	n.273G>A		non_coding_transcript_exon_variant	3/4
FLNC	NM_001127487.2	c.5570-12C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.5669-12C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.5570-12C>T		splice_polypyrimidine_tract_variant, intron_variant		1		A1
FLNC-AS1	ENST00000469965.1	n.273G>A		non_coding_transcript_exon_variant	3/4	4

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4190 AN: 152206 Hom.: 93 Cov.: 33

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0308

Gnomad FIN AF: 0.0811

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0181

GnomAD3 exomes AF: 0.0312 AC: 7794 AN: 249420 Hom.: 208 AF XY: 0.0318 AC XY: 4309 AN XY: 135356

Gnomad AFR exome AF: 0.00594

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0204

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0303

Gnomad FIN exome AF: 0.0765

Gnomad NFE exome AF: 0.0388

Gnomad OTH exome AF: 0.0278

GnomAD4 exome AF: 0.0343 AC: 50078 AN: 1461596 Hom.: 1057 Cov.: 34 AF XY: 0.0346 AC XY: 25148 AN XY: 727108

Gnomad4 AFR exome AF: 0.00469

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.0192

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0311

Gnomad4 FIN exome AF: 0.0710

Gnomad4 NFE exome AF: 0.0367

Gnomad4 OTH exome AF: 0.0269

GnomAD4 genome AF: 0.0275 AC: 4189 AN: 152324 Hom.: 93 Cov.: 33 AF XY: 0.0291 AC XY: 2170 AN XY: 74482

Gnomad4 AFR AF: 0.00642

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0309

Gnomad4 FIN AF: 0.0811

Gnomad4 NFE AF: 0.0377

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0318 Hom.: 16

Bravo AF: 0.0210

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	5669-12C>T in intron 34 of FLNC: This variant is not expected to have clinical s ignificance because it has been identified in 3.5% (300/8532) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs79790270). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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- -

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	-0.71
CADD	Benign	6.4
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.030
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: rs79790270; hg19: chr7-128491497;