rs370589662

Positions:

• chr7-128854191-C-G
• chr7-128854191-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP6 BS2

The NM_001458.5(FLNC):​c.6702C>G​(p.Phe2234Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,455,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.729

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 Likely_benign. Variant got -4 ACMG points.

• 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.
• BP6: Variant 7-128854191-C-G is Benign according to our data. Variant chr7-128854191-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1446278.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.6702C>G	p.Phe2234Leu	missense_variant	40/48	ENST00000325888.13	NP_001449.3
FLNC-AS1	NR_149055.1	n.103-794G>C		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.6603C>G	p.Phe2201Leu	missense_variant	39/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.6702C>G	p.Phe2234Leu	missense_variant	40/48	1	NM_001458.5	ENSP00000327145	P3
FLNC	ENST00000346177.6	c.6603C>G	p.Phe2201Leu	missense_variant	39/47	1		ENSP00000344002	A1
FLNC-AS1	ENST00000469965.1	n.103-794G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000413 AC: 1 AN: 241936 Hom.: 0 AF XY: 0.00000756 AC XY: 1 AN XY: 132278

Gnomad AFR exome AF: 0.0000673

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 AF: 0.0000158 AC: 23 AN: 1455840 Hom.: 0 Cov.: 34 AF XY: 0.00000829 AC XY: 6 AN XY: 723710

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2023

The p.F2234L variant (also known as c.6702C>G), located in coding exon 40 of the FLNC gene, results from a C to G substitution at nucleotide position 6702. The phenylalanine at codon 2234 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	8.4
DANN	Benign	0.90
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.94	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.95	N;N
REVEL	Uncertain	0.61
Sift	Benign	0.72	T;T
Sift4G	Uncertain	0.010	D;D
Polyphen		0.42	B;B
Vest4		0.79
MutPred		0.79		Loss of sheet (P = 0.1158);.;
MVP		0.92
MPC		0.83
ClinPred		0.085	T
GERP RS		-4.5
Varity_R		0.042
gMVP		0.59

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: rs370589662; hg19: chr7-128494245;