rs1362841989

Positions:

• chr7-128854137-C-A
• chr7-128854137-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.6648C>A​(p.Asp2216Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2216N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.637

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 in gene, where missense usually causes diseases (based on misZ statistic), FLNC. . Gene score misZ 2.789 (greater than the threshold 3.09). Trascript score misZ 5.9457 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, heart conduction disease, familial isolated restrictive cardiomyopathy, hypertrophic cardiomyopathy 26, distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09835863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.6648C>A	p.Asp2216Glu	missense_variant	40/48	ENST00000325888.13
FLNC-AS1	NR_149055.1	n.103-740G>T		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.6549C>A	p.Asp2183Glu	missense_variant	39/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.6648C>A	p.Asp2216Glu	missense_variant	40/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.6549C>A	p.Asp2183Glu	missense_variant	39/47	1		A1
FLNC-AS1	ENST00000469965.1	n.103-740G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460334 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726482

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.23
Sift	Benign	0.086	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.0	B;B
Vest4		0.12
MutPred		0.25		Gain of loop (P = 0.1081);.;
MVP		0.38
MPC		0.65
ClinPred		0.41	T
GERP RS		4.8
Varity_R		0.045
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs1362841989; hg19: chr7-128494191;