rs146953558

Variant names:

• chr7-128845186-C-T
• rs146953558
• NM_001458.5:c.3721C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-128845186-C-T
• chr7-128845186-C-A
• chr7-128845186-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):​c.3721C>T​(p.Arg1241Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00865 in 1,613,962 control chromosomes in the GnomAD database, including 78 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. R1241H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0069 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (67 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.819
• Publications: 21 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=0.0095562935).
• BP6: Variant 7-128845186-C-T is Benign according to our data. Variant chr7-128845186-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00693 (1055/152346) while in subpopulation NFE AF = 0.0111 (752/68038). AF 95% confidence interval is 0.0104. There are 11 homozygotes in GnomAd4. There are 544 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1055 AD gene.

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.3721C>T	p.Arg1241Cys	missense	Exon 21 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.3721C>T	p.Arg1241Cys	missense	Exon 21 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.3721C>T	p.Arg1241Cys	missense	Exon 21 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.3721C>T	p.Arg1241Cys	missense	Exon 21 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.3718C>T	p.Arg1240Cys	missense	Exon 21 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.00694 AC: 1056 AN: 152228 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00597 AC: 1479 AN: 247646 AF XY: 0.00619

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.00942

Gnomad OTH exome AF: 0.00512

GnomAD4 exome AF: 0.00883 AC: 12901 AN: 1461616 Hom.: 67 Cov.: 34 AF XY: 0.00865 AC XY: 6290 AN XY: 727130

African (AFR) AF: 0.00119 AC: 40 AN: 33480

American (AMR) AF: 0.00148 AC: 66 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26136

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.00218 AC: 188 AN: 86256

European-Finnish (FIN) AF: 0.0114 AC: 604 AN: 53152

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0104 AC: 11569 AN: 1112008

Other (OTH) AF: 0.00662 AC: 400 AN: 60392

GnomAD4 genome AF: 0.00693 AC: 1055 AN: 152346 Hom.: 11 Cov.: 32 AF XY: 0.00730 AC XY: 544 AN XY: 74502

African (AFR) AF: 0.00137 AC: 57 AN: 41578

American (AMR) AF: 0.00261 AC: 40 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.0133 AC: 141 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 752 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00873 Hom.: 25

Bravo AF: 0.00589

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00115 AC: 5

ESP6500EA AF: 0.00951 AC: 81

ExAC AF: 0.00624 AC: 756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00741

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.82
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.56
Sift	Benign	0.037	D
Sift4G	Benign	0.061	T
Polyphen		0.10	B
Vest4		0.60
MVP		0.66
MPC		1.1
ClinPred		0.019	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.18
gMVP		0.59
Mutation Taster		=92/8	polymorphism

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: rs146953558; hg19: chr7-128485240; COSMIC: COSV57966247; COSMIC: COSV57966247;