7-128855284-C-A

Variant names:

• chr7-128855284-C-A
• rs3816885
• NM_001458.5:c.7221C>A

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.7221C>A​(p.Asp2407Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D2407D) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.38
• Publications: 19 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=0.19570953).

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.7221C>A	p.Asp2407Glu	missense	Exon 43 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.7122C>A	p.Asp2374Glu	missense	Exon 42 of 47	NP_001120959.1	Q14315-2
	FLNC-AS1	NR_149055.1		n.103-1887G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.7221C>A	p.Asp2407Glu	missense	Exon 43 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.7122C>A	p.Asp2374Glu	missense	Exon 42 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.7119C>A	p.Asp2373Glu	missense	Exon 42 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152078 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152078 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74286

African (AFR) AF: 0.00 AC: 0 AN: 41356

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 4695

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.0020
DANN	Benign	0.80
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	L
PhyloP100		-6.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.33
Sift	Benign	0.15	T
Sift4G	Benign	0.40	T
Polyphen		0.053	B
Vest4		0.12
MutPred		0.76		Gain of disorder (P = 0.1786)
MVP		0.50
MPC		0.66
ClinPred		0.10	T
GERP RS		-11
Varity_R		0.18
gMVP		0.22
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs3816885; hg19: chr7-128495338;