rs200233856

Positions:

• chr7-128850460-C-A
• chr7-128850460-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001458.5(FLNC):​c.5375C>A​(p.Ala1792Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. A1792V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71

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
• PP2: Missense variant where missense usually causes diseases, FLNC
• BP4: Computational evidence support a benign effect (MetaRNN=0.22387898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.5375C>A	p.Ala1792Glu	missense_variant	32/48	ENST00000325888.13
FLNC-AS1	NR_149055.1	n.316-55G>T		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.5276C>A	p.Ala1759Glu	missense_variant	31/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.5375C>A	p.Ala1792Glu	missense_variant	32/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.5276C>A	p.Ala1759Glu	missense_variant	31/47	1		A1
FLNC-AS1	ENST00000469965.1	n.316-55G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249226 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135222

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ESP6500AA AF: 0.000254 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-0.052
Eigen_PC	Benign	0.097
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.63	N;.
MutationTaster	Benign	0.84	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.014	D;T
Sift4G	Benign	0.65	T;T
Polyphen		0.34	B;B
Vest4		0.40
MVP		0.32
MPC		0.37
ClinPred		0.25	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.26
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs200233856; hg19: chr7-128490514;