7-128854493-G-C

Variant names:

• chr7-128854493-G-C
• rs202223616
• NM_001458.5:c.6808G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001458.5(FLNC):​c.6808G>C​(p.Glu2270Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,584 control chromosomes in the GnomAD database, including 1 homozygotes. 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. E2270K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (1 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.97

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36596727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.6808G>C	p.Glu2270Gln	missense_variant	Exon 41 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.6709G>C	p.Glu2237Gln	missense_variant	Exon 40 of 47		NP_001120959.1
FLNC-AS1	NR_149055.1	n.103-1096C>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.6808G>C	p.Glu2270Gln	missense_variant	Exon 41 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.6709G>C	p.Glu2237Gln	missense_variant	Exon 40 of 47	1		ENSP00000344002.6
FLNC-AS1	ENST00000469965.1	n.103-1096C>G		intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000218 AC: 5 AN: 229546 Hom.: 1 AF XY: 0.0000320 AC XY: 4 AN XY: 124852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000174

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1453584 Hom.: 1 Cov.: 33 AF XY: 0.00000415 AC XY: 3 AN XY: 722394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000471

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.081	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.95	P;D
Vest4		0.23
MutPred		0.38		Loss of phosphorylation at S2272 (P = 0.1256);.;
MVP		0.76
MPC		1.6
ClinPred		0.45	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202223616; hg19: chr7-128494547; COSMIC: COSV105824949;