rs2291560

Variant names:

• chr7-128837418-T-C
• rs2291560
• NM_001458.5:c.720T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-128837418-T-C
• chr7-128837418-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001458.5(FLNC):​c.720T>C​(p.Ile240Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,613,948 control chromosomes in the GnomAD database, including 10,454 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1008 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9446 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.68
• Publications: 14 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-128837418-T-C is Benign according to our data. Variant chr7-128837418-T-C is described in ClinVar as Benign. ClinVar VariationId is 129096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 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.720T>C	p.Ile240Ile	synonymous	Exon 4 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.720T>C	p.Ile240Ile	synonymous	Exon 4 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.720T>C	p.Ile240Ile	synonymous	Exon 4 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.720T>C	p.Ile240Ile	synonymous	Exon 4 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.720T>C	p.Ile240Ile	synonymous	Exon 4 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16947 AN: 152058 Hom.: 1009 Cov.: 33

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0625

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.0963

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.105 AC: 26298 AN: 249724 AF XY: 0.108

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.0477

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.0944

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.112 AC: 164189 AN: 1461772 Hom.: 9446 Cov.: 36 AF XY: 0.113 AC XY: 82425 AN XY: 727192

African (AFR) AF: 0.126 AC: 4233 AN: 33468

American (AMR) AF: 0.0522 AC: 2335 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2817 AN: 26136

East Asian (EAS) AF: 0.116 AC: 4598 AN: 39700

South Asian (SAS) AF: 0.142 AC: 12247 AN: 86258

European-Finnish (FIN) AF: 0.103 AC: 5472 AN: 53382

Middle Eastern (MID) AF: 0.0869 AC: 501 AN: 5768

European-Non Finnish (NFE) AF: 0.113 AC: 125125 AN: 1111948

Other (OTH) AF: 0.114 AC: 6861 AN: 60388

GnomAD4 genome AF: 0.112 AC: 16972 AN: 152176 Hom.: 1008 Cov.: 33 AF XY: 0.111 AC XY: 8226 AN XY: 74408

African (AFR) AF: 0.125 AC: 5170 AN: 41490

American (AMR) AF: 0.0623 AC: 954 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 410 AN: 3468

East Asian (EAS) AF: 0.111 AC: 576 AN: 5170

South Asian (SAS) AF: 0.154 AC: 744 AN: 4826

European-Finnish (FIN) AF: 0.0963 AC: 1023 AN: 10620

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7739 AN: 67978

Other (OTH) AF: 0.124 AC: 263 AN: 2114

Alfa AF: 0.111 Hom.: 1427

Bravo AF: 0.108

Asia WGS AF: 0.153 AC: 532 AN: 3478

EpiCase AF: 0.118

EpiControl AF: 0.111

ClinVar

ClinVar submissions

Significance: 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;CN239310:Dilated Cardiomyopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.47
DANN	Benign	0.60
PhyloP100		-2.7
Mutation Taster		=100/0	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: rs2291560; hg19: chr7-128477472; COSMIC: COSV57955931; COSMIC: COSV57955931;