rs2291569

Variant names:

• chr7-128848680-G-A
• rs2291569
• NM_001458.5:c.4700G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-128848680-G-A
• chr7-128848680-G-T
• chr7-128848680-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001458.5(FLNC):​c.4700G>A​(p.Arg1567Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0819 in 1,613,300 control chromosomes in the GnomAD database, including 5,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1567W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.064 (400 hom., cov: 33)
  • Exomes 𝑓: 0.084 (5375 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.51
• Publications: 30 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, ClinGen, Ambry Genetics
• myofibrillar myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• myofibrillar myopathy 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy 26

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• distal myopathy with posterior leg and anterior hand involvement

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008130968).
• BP6: Variant 7-128848680-G-A is Benign according to our data. Variant chr7-128848680-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001458.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.4700G>A	p.Arg1567Gln	missense	Exon 27 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.4700G>A	p.Arg1567Gln	missense	Exon 27 of 47	NP_001120959.1	Q14315-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.4700G>A	p.Arg1567Gln	missense	Exon 27 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.4700G>A	p.Arg1567Gln	missense	Exon 27 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.4697G>A	p.Arg1566Gln	missense	Exon 27 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9812 AN: 152136 Hom.: 401 Cov.: 33

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0437

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.0901

Gnomad FIN AF: 0.0631

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0863

Gnomad OTH AF: 0.0809

GnomAD2 exomes AF: 0.0750 AC: 18657 AN: 248650 AF XY: 0.0778

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0970

Gnomad FIN exome AF: 0.0687

Gnomad NFE exome AF: 0.0870

Gnomad OTH exome AF: 0.0866

GnomAD4 exome AF: 0.0837 AC: 122286 AN: 1461046 Hom.: 5375 Cov.: 35 AF XY: 0.0842 AC XY: 61197 AN XY: 726874

African (AFR) AF: 0.0192 AC: 642 AN: 33480

American (AMR) AF: 0.0373 AC: 1670 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2731 AN: 26134

East Asian (EAS) AF: 0.127 AC: 5036 AN: 39700

South Asian (SAS) AF: 0.0841 AC: 7255 AN: 86254

European-Finnish (FIN) AF: 0.0710 AC: 3738 AN: 52616

Middle Eastern (MID) AF: 0.0735 AC: 424 AN: 5768

European-Non Finnish (NFE) AF: 0.0862 AC: 95821 AN: 1111984

Other (OTH) AF: 0.0823 AC: 4969 AN: 60386

GnomAD4 genome AF: 0.0645 AC: 9820 AN: 152254 Hom.: 400 Cov.: 33 AF XY: 0.0632 AC XY: 4705 AN XY: 74444

African (AFR) AF: 0.0223 AC: 929 AN: 41566

American (AMR) AF: 0.0435 AC: 666 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 398 AN: 3472

East Asian (EAS) AF: 0.114 AC: 588 AN: 5162

South Asian (SAS) AF: 0.0906 AC: 437 AN: 4826

European-Finnish (FIN) AF: 0.0631 AC: 669 AN: 10610

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0863 AC: 5869 AN: 68000

Other (OTH) AF: 0.0838 AC: 177 AN: 2112

Alfa AF: 0.0825 Hom.: 1969

Bravo AF: 0.0610

TwinsUK AF: 0.0895 AC: 332

ALSPAC AF: 0.0893 AC: 344

ESP6500AA AF: 0.0244 AC: 102

ESP6500EA AF: 0.0850 AC: 716

ExAC AF: 0.0762 AC: 9219

Asia WGS AF: 0.103 AC: 360 AN: 3478

EpiCase AF: 0.0907

EpiControl AF: 0.0887

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;na:Dilated Cardiomyopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.38
Sift	Benign	0.067	T
Sift4G	Uncertain	0.028	D
Polyphen		0.91	P
Vest4		0.18
MPC		1.0
ClinPred		0.074	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.43
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2291569; hg19: chr7-128488734; COSMIC: COSV57954403; COSMIC: COSV57954403;