rs35281128

Variant names:

• chr7-128845089-G-A
• rs35281128
• NM_001458.5:c.3624G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-128845089-G-A
• chr7-128845089-G-C

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.3624G>A​(p.Ala1208Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,613,804 control chromosomes in the GnomAD database, including 1,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1208A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.064 (1024 hom., cov: 32)
  • Exomes 𝑓: 0.010 (961 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -7.10
• Publications: 3 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=-0.89).
• BP6: Variant 7-128845089-G-A is Benign according to our data. Variant chr7-128845089-G-A is described in ClinVar as Benign. ClinVar VariationId is 129085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 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.3624G>A	p.Ala1208Ala	synonymous	Exon 21 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.3624G>A	p.Ala1208Ala	synonymous	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.3624G>A	p.Ala1208Ala	synonymous	Exon 21 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.3624G>A	p.Ala1208Ala	synonymous	Exon 21 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.3621G>A	p.Ala1207Ala	synonymous	Exon 21 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.0643 AC: 9780 AN: 152076 Hom.: 1022 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0355

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.0445

GnomAD2 exomes AF: 0.0220 AC: 5494 AN: 249516 AF XY: 0.0198

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.00970

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0119

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.0104 AC: 15263 AN: 1461610 Hom.: 961 Cov.: 34 AF XY: 0.0107 AC XY: 7770 AN XY: 727132

African (AFR) AF: 0.214 AC: 7180 AN: 33480

American (AMR) AF: 0.0113 AC: 504 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0186 AC: 739 AN: 39700

South Asian (SAS) AF: 0.0388 AC: 3350 AN: 86258

European-Finnish (FIN) AF: 0.000151 AC: 8 AN: 53148

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5768

European-Non Finnish (NFE) AF: 0.00206 AC: 2294 AN: 1112008

Other (OTH) AF: 0.0189 AC: 1141 AN: 60390

GnomAD4 genome AF: 0.0643 AC: 9792 AN: 152194 Hom.: 1024 Cov.: 32 AF XY: 0.0618 AC XY: 4600 AN XY: 74414

African (AFR) AF: 0.214 AC: 8894 AN: 41492

American (AMR) AF: 0.0250 AC: 382 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0162 AC: 84 AN: 5186

South Asian (SAS) AF: 0.0353 AC: 170 AN: 4818

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00235 AC: 160 AN: 68014

Other (OTH) AF: 0.0440 AC: 93 AN: 2112

Alfa AF: 0.0516 Hom.: 631

Bravo AF: 0.0713

Asia WGS AF: 0.0490 AC: 169 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	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	-0.89
CADD	Benign	0.57
DANN	Benign	0.39
PhyloP100		-7.1
Mutation Taster		=84/16	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: rs35281128; hg19: chr7-128485143; COSMIC: COSV100367664; COSMIC: COSV100367664;