7-128850072-T-G

Variant names:

• chr7-128850072-T-G
• rs751650734
• NM_001458.5:c.5296T>G

Variant summary

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

The NM_001458.5(FLNC):​c.5296T>G​(p.Trp1766Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. W1766R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNC NM_001458.5 missense, splice_region
• Scores: Splicing: ADA: 0.003345
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.32
• Publications: 2 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.5296T>G	p.Trp1766Gly	missense_variant, splice_region_variant	Exon 31 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.5200-312T>G		intron_variant	Intron 30 of 46		NP_001120959.1
FLNC-AS1	NR_149055.1	n.*90A>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.5296T>G	p.Trp1766Gly	missense_variant, splice_region_variant	Exon 31 of 48	1	NM_001458.5	ENSP00000327145.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Benign	0.87
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.49
Sift	Benign	0.81	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.79
MutPred		0.28		Gain of relative solvent accessibility (P = 0.005);
MVP		0.95
MPC		0.49
ClinPred		0.75	D
GERP RS		5.1
Varity_R		0.41
gMVP		0.56
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0033
dbscSNV1_RF	Benign	0.080
SpliceAI score (max)		0.10		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: rs751650734; hg19: chr7-128490126;