7-128852957-G-C

Variant names:

• chr7-128852957-G-C
• rs747196571
• NM_001458.5:c.6134G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001458.5(FLNC):​c.6134G>C​(p.Arg2045Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,244 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2045Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18
• Publications: 3 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-AS1 (HGNC:53474): (FLNC antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.6134G>C	p.Arg2045Pro	missense	Exon 37 of 48	NP_001449.3
	FLNC	NM_001127487.2		c.6035G>C	p.Arg2012Pro	missense	Exon 36 of 47	NP_001120959.1
	FLNC-AS1	NR_149055.1		n.215+328C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.6134G>C	p.Arg2045Pro	missense	Exon 37 of 48	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.6035G>C	p.Arg2012Pro	missense	Exon 36 of 47	ENSP00000344002.6
	FLNC	ENST00000950263.1		c.6032G>C	p.Arg2011Pro	missense	Exon 36 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249200 AF XY: 0.00

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461244 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726926

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.93	P
Vest4		0.81
MutPred		0.67		Loss of catalytic residue at R2045 (P = 0.0103)
MVP		0.92
MPC		1.9
ClinPred		0.97	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.80
gMVP		0.82
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs747196571; hg19: chr7-128493011;