chr7-128830671-C-A

Variant names:

• chr7-128830671-C-A
• NM_001458.5:c.34C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001458.5(FLNC):​c.34C>A​(p.Leu12Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.656

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 0 ACMG points.

• PM1: In a region_of_interest Actin-binding (size 258) in uniprot entity FLNC_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_001458.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044603854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.34C>A	p.Leu12Ile	missense_variant	Exon 1 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.34C>A	p.Leu12Ile	missense_variant	Exon 1 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.34C>A	p.Leu12Ile	missense_variant	Exon 1 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.34C>A	p.Leu12Ile	missense_variant	Exon 1 of 47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.69	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.12	N;N
REVEL	Benign	0.17
Sift	Benign	0.46	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0	B;B
Vest4		0.14
MutPred		0.22		Loss of phosphorylation at Y7 (P = 0.1902);Loss of phosphorylation at Y7 (P = 0.1902);
MVP		0.23
MPC		1.1
ClinPred		0.060	T
GERP RS		-0.017
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.046
gMVP		0.099

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: chr7-128470725;