rs367931139

Positions:

• chr7-128846390-C-A
• chr7-128846390-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PP2 PP3_Moderate BP6

The NM_001458.5(FLNC):​c.4054C>A​(p.Arg1352Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1352R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.73

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNC. . Gene score misZ 2.789 (greater than the threshold 3.09). Trascript score misZ 5.9457 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, heart conduction disease, familial isolated restrictive cardiomyopathy, hypertrophic cardiomyopathy 26, distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• BP6: Variant 7-128846390-C-A is Benign according to our data. Variant chr7-128846390-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1737399.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.4054C>A	p.Arg1352Ser	missense_variant	23/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.4054C>A	p.Arg1352Ser	missense_variant	23/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.4054C>A	p.Arg1352Ser	missense_variant	23/48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.4054C>A	p.Arg1352Ser	missense_variant	23/47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 247142 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134360

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459054 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 725958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.4054C>A (p.R1352S) alteration is located in exon 23 (coding exon 23) of the FLNC gene. This alteration results from a C to A substitution at nucleotide position 4054, causing the arginine (R) at amino acid position 1352 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.67		Gain of phosphorylation at R1352 (P = 0.0677);Gain of phosphorylation at R1352 (P = 0.0677);
MVP		0.92
MPC		0.62
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.87
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs367931139; hg19: chr7-128486444;