7-128848818-C-T

Variant names:

• chr7-128848818-C-T
• rs148545460
• NM_001458.5:c.4763C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001458.5(FLNC):​c.4763C>T​(p.Ala1588Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1588G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.10
• Publications: 6 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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics, G2P
• myofibrillar myopathy 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
• hypertrophic cardiomyopathy 26

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• distal myopathy with posterior leg and anterior hand involvement

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20178193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.4763C>T	p.Ala1588Val	missense_variant	Exon 28 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.4763C>T	p.Ala1588Val	missense_variant	Exon 28 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.4763C>T	p.Ala1588Val	missense_variant	Exon 28 of 48	1	NM_001458.5	ENSP00000327145.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249274 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.36	N;N
PhyloP100		4.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.27	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.58	P;D
Vest4		0.20
MutPred		0.42		Gain of methylation at K1587 (P = 0.0408);Gain of methylation at K1587 (P = 0.0408);
MVP		0.70
MPC		0.90
ClinPred		0.77	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.41
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs148545460; hg19: chr7-128488872;