rs76046880

Variant names:

• chr7-128840612-C-T
• rs76046880
• NM_001458.5:c.1614C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-128840612-C-T
• chr7-128840612-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001458.5(FLNC):​c.1614C>T​(p.Tyr538Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,614,176 control chromosomes in the GnomAD database, including 1,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (95 hom., cov: 33)
  • Exomes 𝑓: 0.034 (1049 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0560
• Publications: 4 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=-0.49).
• BP6: Variant 7-128840612-C-T is Benign according to our data. Variant chr7-128840612-C-T is described in ClinVar as Benign. ClinVar VariationId is 129082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.056 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0293 (4467/152302) while in subpopulation NFE AF = 0.0379 (2576/68004). AF 95% confidence interval is 0.0367. There are 95 homozygotes in GnomAd4. There are 2317 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4467 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.1614C>T	p.Tyr538Tyr	synonymous	Exon 10 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.1614C>T	p.Tyr538Tyr	synonymous	Exon 10 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.1614C>T	p.Tyr538Tyr	synonymous	Exon 10 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.1614C>T	p.Tyr538Tyr	synonymous	Exon 10 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.1614C>T	p.Tyr538Tyr	synonymous	Exon 10 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4468 AN: 152184 Hom.: 95 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0811

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0313 AC: 7808 AN: 249564 AF XY: 0.0316

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0765

Gnomad NFE exome AF: 0.0387

Gnomad OTH exome AF: 0.0282

GnomAD4 exome AF: 0.0343 AC: 50075 AN: 1461874 Hom.: 1049 Cov.: 34 AF XY: 0.0345 AC XY: 25065 AN XY: 727240

African (AFR) AF: 0.00863 AC: 289 AN: 33480

American (AMR) AF: 0.0125 AC: 561 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 496 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0276 AC: 2379 AN: 86258

European-Finnish (FIN) AF: 0.0710 AC: 3792 AN: 53410

Middle Eastern (MID) AF: 0.0140 AC: 81 AN: 5768

European-Non Finnish (NFE) AF: 0.0367 AC: 40815 AN: 1112002

Other (OTH) AF: 0.0275 AC: 1659 AN: 60396

GnomAD4 genome AF: 0.0293 AC: 4467 AN: 152302 Hom.: 95 Cov.: 33 AF XY: 0.0311 AC XY: 2317 AN XY: 74466

African (AFR) AF: 0.0111 AC: 460 AN: 41576

American (AMR) AF: 0.0197 AC: 301 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0286 AC: 138 AN: 4828

European-Finnish (FIN) AF: 0.0811 AC: 861 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0379 AC: 2576 AN: 68004

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0330 Hom.: 79

Bravo AF: 0.0236

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.0344

EpiControl AF: 0.0324

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.7
DANN	Benign	0.56
PhyloP100		-0.056
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=99/1	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: rs76046880; hg19: chr7-128480666;