rs28379666

Variant names:

• chr7-128858463-C-T
• rs28379666
• NM_001458.5:c.8118C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001458.5(FLNC):​c.8118C>T​(p.Leu2706Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 1,608,226 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (46 hom., cov: 31)
  • Exomes 𝑓: 0.0040 (113 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0650

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-AS1 (HGNC:53474): (FLNC antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 7-128858463-C-T is Benign according to our data. Variant chr7-128858463-C-T is described in ClinVar as [Benign]. Clinvar id is 129100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128858463-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.065 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0153 (2330/152008) while in subpopulation AFR AF= 0.044 (1820/41364). AF 95% confidence interval is 0.0423. There are 46 homozygotes in gnomad4. There are 1090 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2330 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.8118C>T	p.Leu2706Leu	synonymous_variant	Exon 48 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.8019C>T	p.Leu2673Leu	synonymous_variant	Exon 47 of 47		NP_001120959.1
FLNC-AS1	NR_149055.1	n.102+4062G>A		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.8118C>T	p.Leu2706Leu	synonymous_variant	Exon 48 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.8019C>T	p.Leu2673Leu	synonymous_variant	Exon 47 of 47	1		ENSP00000344002.6
FLNC-AS1	ENST00000469965.1	n.102+4062G>A		intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2326 AN: 151890 Hom.: 46 Cov.: 31

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0153

Gnomad SAS AF: 0.0279

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00949 AC: 2368 AN: 249484 Hom.: 56 AF XY: 0.00996 AC XY: 1348 AN XY: 135354

Gnomad AFR exome AF: 0.0459

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0121

Gnomad SAS exome AF: 0.0343

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.00644

GnomAD4 exome AF: 0.00403 AC: 5863 AN: 1456218 Hom.: 113 Cov.: 32 AF XY: 0.00460 AC XY: 3331 AN XY: 724280

Gnomad4 AFR exome AF: 0.0261

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0166

Gnomad4 SAS exome AF: 0.0217

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00188

Gnomad4 OTH exome AF: 0.00523

GnomAD4 genome AF: 0.0153 AC: 2330 AN: 152008 Hom.: 46 Cov.: 31 AF XY: 0.0147 AC XY: 1090 AN XY: 74310

Gnomad4 AFR AF: 0.0440

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0153

Gnomad4 SAS AF: 0.0279

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00281

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00837 Hom.: 10

Bravo AF: 0.0166

EpiCase AF: 0.00267

EpiControl AF: 0.00284

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jul 22, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 26, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.7
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs28379666; hg19: chr7-128498517; COSMIC: COSV99972435; COSMIC: COSV99972435;