7-128858174-C-G

Variant names:

• chr7-128858174-C-G
• rs368849358
• NM_001458.5:c.7947C>G

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.7947C>G​(p.Phe2649Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,382 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. F2649S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.44
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22841033).

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.7947C>G	p.Phe2649Leu	missense	Exon 47 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.7848C>G	p.Phe2616Leu	missense	Exon 46 of 47	NP_001120959.1	Q14315-2
	FLNC-AS1	NR_149055.1		n.102+4351G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.7947C>G	p.Phe2649Leu	missense	Exon 47 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.7848C>G	p.Phe2616Leu	missense	Exon 46 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.7845C>G	p.Phe2615Leu	missense	Exon 46 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412382 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 705360

African (AFR) AF: 0.00 AC: 0 AN: 32754

American (AMR) AF: 0.00 AC: 0 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 39454

South Asian (SAS) AF: 0.00 AC: 0 AN: 85004

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067706

Other (OTH) AF: 0.00 AC: 0 AN: 58708

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.7	L
PhyloP100		-2.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.47
Sift	Benign	0.24	T
Sift4G	Benign	0.12	T
Polyphen		0.055	B
Vest4		0.46
MutPred		0.46		Loss of methylation at K2653 (P = 0.0631)
MVP		0.74
MPC		0.84
ClinPred		0.71	D
GERP RS		-0.029
Varity_R		0.67
gMVP		0.59
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs368849358; hg19: chr7-128498228;