rs201926772

Positions:

• chr7-128850060-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001458.5(FLNC):​c.5284C>T​(p.Arg1762Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,540,606 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (2 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.581

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 Benign. Variant got -12 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.031011462).
• BP6: Variant 7-128850060-C-T is Benign according to our data. Variant chr7-128850060-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472100.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000158 (219/1388298) while in subpopulation MID AF= 0.0016 (9/5624). AF 95% confidence interval is 0.000834. There are 2 homozygotes in gnomad4_exome. There are 123 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.5284C>T	p.Arg1762Cys	missense_variant	31/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.5200-324C>T		intron_variant			NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.5284C>T	p.Arg1762Cys	missense_variant	31/48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.5200-324C>T		intron_variant		1		ENSP00000344002.6

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000285 AC: 41 AN: 143778 Hom.: 0 AF XY: 0.000321 AC XY: 25 AN XY: 77882

Gnomad AFR exome AF: 0.000392

Gnomad AMR exome AF: 0.0000403

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000785

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000158 AC: 219 AN: 1388298 Hom.: 2 Cov.: 32 AF XY: 0.000179 AC XY: 123 AN XY: 685798

Gnomad4 AFR exome AF: 0.000346

Gnomad4 AMR exome AF: 0.0000556

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000931

Gnomad4 FIN exome AF: 0.0000554

Gnomad4 NFE exome AF: 0.0000870

Gnomad4 OTH exome AF: 0.000465

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74480

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000302

ESP6500AA AF: 0.000250 AC: 1

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000186 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	FLNC: BP4 -

Hypertrophic cardiomyopathy 26 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.5284C>T (p.Arg1762Cys) in FLNC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant has been submitted to ClinVar with conflicting interpretations of Uncertain Significance/Likely Benign. The p.Arg1762Cys variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.02512% is reported in gnomAD. The amino acid Arg at position 1762 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Arg1762Cys in FLNC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. For these reasons, this variant has been classified as Uncertain Significance . -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Benign	0.057	T
Sift4G	Uncertain	0.046	D
Polyphen		0.0	B
Vest4		0.11
MVP		0.26
MPC		0.38
ClinPred		0.018	T
GERP RS		2.5
Varity_R		0.071
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201926772; hg19: chr7-128490114;