rs1334300883

Positions:

• chr7-128855201-G-A
• chr7-128855201-G-C
• chr7-128855201-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001458.5(FLNC):​c.7138G>A​(p.Asp2380Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNC NM_001458.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80

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 Uncertain_significance. Variant got 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36361545).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.7138G>A	p.Asp2380Asn	missense_variant, splice_region_variant	43/48	ENST00000325888.13	NP_001449.3
FLNC-AS1	NR_149055.1	n.103-1804C>T		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.7039G>A	p.Asp2347Asn	missense_variant, splice_region_variant	42/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.7138G>A	p.Asp2380Asn	missense_variant, splice_region_variant	43/48	1	NM_001458.5	ENSP00000327145	P3
FLNC	ENST00000346177.6	c.7039G>A	p.Asp2347Asn	missense_variant, splice_region_variant	42/47	1		ENSP00000344002	A1
FLNC-AS1	ENST00000469965.1	n.103-1804C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Oct 22, 2021

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. 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: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 2380 of the FLNC protein (p.Asp2380Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.39
Sift	Benign	0.46	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.0090	B;D
Vest4		0.21
MutPred		0.45		Loss of phosphorylation at Y2381 (P = 0.1027);.;
MVP		0.85
MPC		0.92
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.47
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-128495255;