rs975517733

Positions:

• chr7-128841482-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001458.5(FLNC):​c.2036C>T​(p.Pro679Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:2
• Conservation: PhyloP100: 1.69

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.2036C>T	p.Pro679Leu	missense_variant	13/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.2036C>T	p.Pro679Leu	missense_variant	13/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.2036C>T	p.Pro679Leu	missense_variant	13/48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.2036C>T	p.Pro679Leu	missense_variant	13/47	1		ENSP00000344002.6
FLNC	ENST00000388853.3	n.152C>T		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy;C1836050:Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement Other:2

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 12-08-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 05-29-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 22, 2019

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 539414). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 679 of the FLNC protein (p.Pro679Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Uncertain	0.61
Sift	Benign	0.034	D;D
Sift4G	Uncertain	0.037	D;D
Polyphen		0.74	P;D
Vest4		0.53
MutPred		0.60		Loss of disorder (P = 0.03);Loss of disorder (P = 0.03);
MVP		0.73
MPC		0.97
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.35
gMVP		0.71

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: rs975517733; hg19: chr7-128481536;