rs532143625

Variant names:

• chr7-128837983-A-G
• rs532143625
• NM_001458.5:c.970-4A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_001458.5(FLNC):​c.970-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: FLNC NM_001458.5 splice_region, intron
• Scores: Splicing: ADA: 0.8501
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:4
• Conservation: PhyloP100: -0.341
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics, G2P
• myofibrillar myopathy 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
• hypertrophic cardiomyopathy 26

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• distal myopathy with posterior leg and anterior hand involvement

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP5: Variant 7-128837983-A-G is Pathogenic according to our data. Variant chr7-128837983-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 432231.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 21 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001458.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.970-4A>G		splice_region intron	N/A	NP_001449.3
	FLNC	NM_001127487.2		c.970-4A>G		splice_region intron	N/A	NP_001120959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.970-4A>G		splice_region intron	N/A	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.970-4A>G		splice_region intron	N/A	ENSP00000344002.6
	FLNC	ENST00000714183.1		c.970-4A>G		splice_region intron	N/A	ENSP00000519472.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152044 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 249292 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000208 AC: 304 AN: 1461278 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 137 AN XY: 726956

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000268 AC: 298 AN: 1111500

Other (OTH) AF: 0.0000828 AC: 5 AN: 60378

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152044 Hom.: 0 Cov.: 33 AF XY: 0.000162 AC XY: 12 AN XY: 74258

African (AFR) AF: 0.0000966 AC: 4 AN: 41392

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000173 Hom.: 0

Bravo AF: 0.0000982

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Jun 13, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with cardiomyopathy, including peripartum cardiomyopathy, dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) in published literature; several patients harbored additional cardiogenetic variants (PMID: 32112656, 34587765, 37164047, 38761081); A published functional study demonstrates a damaging effect as c.970-4A>G activated the cryptic SAS, introducing a 3-bp insertion which results in protein truncation and nonsense mediated decay; patch clamp studies also showed irregular spontaneous action potentials, increased action potential duration, and increased sodium late current (PMID: 37164047); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32112656, 37164047, 34587765, 38761081, 38657199)

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FLNC: PVS1, PP1:Moderate, PS4:Moderate

FLNC-related disorder Pathogenic:1 Uncertain:1

Sep 03, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3_Moderate, PP1

Jan 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FLNC c.970-4A>G variant is predicted to interfere with splicing. This variant has been reported in an individual with dilated cardiomyopathy (Verdonschot et al. 2020. PubMed ID: 32112656, table 1) and in an additional large cohort study of patients with FLNC truncating variants and varied cardiac phenotypes (Gigli et al. 2021. PubMed ID: 34587765). An outside laboratory indicated this variant was detected in 4 probands with segregation in affected family members; however, additional details were not provided (https://www.ncbi.nlm.nih.gov/clinvar/variation/432231/). This variant is reported in 0.010% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Cardiomyopathy Pathogenic:1

Jan 10, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arrhythmogenic cardiomyopathy Pathogenic:1

Oct 28, 2022

Roden Lab, Vanderbilt University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Truncating variants in FLNC are reported to cause a highly penetrant form of arrhythmogenic cardiomyopathy (Gigli, Circulation, 2021). The FLNC c.970-4A>G variant was identified in 4 probands with arrhythmogenic cardiomyopathy, and the variant cosegregated with phenotype in heterozygous family members. Computational tools predicted that the variant activated a cryptic splice acceptor site 3 nucleotides adjacent to the canonical site, leading to inclusion of an in-frame premature termination codon in the mature mRNA. Functional studies confirmed this molecular event in peripheral blood and iPSC-CM RNA analyses, provoking a phenotype consistent with other truncating FLNC variants. These data collectively support criteria to classify FLNC c.970-4A>G as pathogenic.

Primary familial dilated cardiomyopathy Pathogenic:1

Mar 28, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FLNC c.970-4A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 3' acceptor site. One predicts the variant abolishes a 3' acceptor site. Four predict the variant creates a 3' cryptic acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by creating a cryptic splice acceptor site and introducing a 3-bp insertion containing a premature termination codon (ONeill_2023). The variant allele was found at a frequency of 2.4e-05 in 249292 control chromosomes. c.970-4A>G has been reported in the literature in multiple individuals affected with dilated cardiomyopathy and was shown to segregate with disease in at least one family (e.g., ONeill_2023). The following publication has been ascertained in the context of this evaluation (PMID: 37164047).ClinVar contains an entry for this variant (Variation ID: 432231). Based on the evidence outlined above, the variant was classified as pathogenic.

Primary dilated cardiomyopathy Pathogenic:1

Apr 24, 2024

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FLNC c.970-4A>G variant occurs in a splice region and has been shown to result in a splicing defect leading to premature termination of the protein (PMID: 37164047). This variant has been identified in individuals with cardiomyopathy (PMID: 32112656; 34587765; 37164047). Further, this variant has been shown to segregate with disease in a family (PMID: 37164047). A functional study conducted in patient-derived cardiomyocytes demonstrated that this variant impacts action potential rhythm (PMID: 37164047). The highest frequency of this allele in the Genome Aggregation Database is 0.0002654 in the European (non-Finnish) population (version 4.1.0). This frequency is high but may be consistent with reduced penetrance. Based on the available evidence, the c.970-4A>G variant is classified as likely pathogenic for dilated cardiomyopathy.

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Pathogenic:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 5 of the FLNC gene. It does not directly change the encoded amino acid sequence of the FLNC protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs532143625, gnomAD 0.009%). This variant has been observed in individuals with clinical features of FLNC-related conditions (PMID: 32112656, 34587765, 37164047; internal data). ClinVar contains an entry for this variant (Variation ID: 432231). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 37164047). For these reasons, this variant has been classified as Pathogenic.

Myofibrillar myopathy 5 Uncertain:1

Nov 11, 2021

Molecular Genetics, Royal Melbourne Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in the splice region of the acceptor site of intron 5 of FLNC. The variant is present in a large population cohort at a frequency of 0.005% (rs532143625, 15/280,590 alleles, 0 homozygotes in gnomAD v2.1). It has been classified as a variant of uncertain significance and pathogenic previously (ClinVar, LOVD). The variant has been identified in at least two probands with dilated cardiomyopathy (PMID: 32112656, Shariant), and compound heterozygous with a second pathogenic allele in an individual with cardiomyopathy (https://doi.org/10.1161/res.127.suppl_1.454). The nucleotide is not conserved (100 vertebrates, UCSC), and multiple lines of computational evidence predict a impact on splicing (SpliceAI, MaxEntScan, NNSplice). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE . Following criteria are met: PP3.

Cardiovascular phenotype Uncertain:1

Feb 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.970-4A>G intronic variant results from an A to G substitution 4 nucleotides before coding exon 6 in the FLNC gene. This variant has been detected in probands with dilated cardiomyopathy (DCM) and/or arrhythmogenic cardiomyopathy, and has shown some segregation with disease features in families; however, in some cases, clinical details were limited or additional variants in cardiac-related genes were detected (Verdonschot JAJ et al. Hum Mutat, 2020 06;41:1091-1111; Gigli M et al. Circulation. 2021 Nov;144(20):1600-1611; O'Neill MJ et al. Heart Rhythm. 2023 Aug;20(8):1158-1166). RNA studies by one group have indicated that this alteration results in abnormal splicing (O'Neill MJ et al. Heart Rhythm. 2023 Aug;20(8):1158-1166). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	20
DANN	Benign	0.56
PhyloP100		-0.34
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs532143625; hg19: chr7-128478037;