chr7-128848053-A-G

Variant names:

• chr7-128848053-A-G
• rs1022106059
• NM_001458.5:c.4565A>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_001458.5(FLNC):​c.4565A>G​(p.Gln1522Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,605,386 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: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 9.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 7-128848053-A-G is Benign according to our data. Variant chr7-128848053-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472069.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.4565A>G	p.Gln1522Arg	missense_variant	Exon 26 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.4565A>G	p.Gln1522Arg	missense_variant	Exon 26 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.4565A>G	p.Gln1522Arg	missense_variant	Exon 26 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.4565A>G	p.Gln1522Arg	missense_variant	Exon 26 of 47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000865 AC: 2 AN: 231294 Hom.: 0 AF XY: 0.0000159 AC XY: 2 AN XY: 125934

Gnomad AFR exome AF: 0.000145

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: 0.00000206 AC: 3 AN: 1453216 Hom.: 0 Cov.: 36 AF XY: 0.00000277 AC XY: 2 AN XY: 722144

Gnomad4 AFR exome AF: 0.0000901

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74334

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Jan 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1522R variant (also known as c.4565A>G), located in coding exon 26 of the FLNC gene, results from an A to G substitution at nucleotide position 4565. The glutamine at codon 1522 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well 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

Aug 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.74	P;D
Vest4		0.56
MutPred		0.58		Gain of MoRF binding (P = 0.0523);Gain of MoRF binding (P = 0.0523);
MVP		0.81
MPC		0.53
ClinPred		0.69	D
GERP RS		5.1
Varity_R		0.49
gMVP		0.42

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: rs1022106059; hg19: chr7-128488107; COSMIC: COSV57957988; COSMIC: COSV57957988;