NM_001458.5:c.5669-12C>T

Variant names:

• chr7-128851443-C-T
• rs79790270
• NM_001458.5:c.5669-12C>T

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.5669-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,613,920 control chromosomes in the GnomAD database, including 1,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (93 hom., cov: 33)
  • Exomes 𝑓: 0.034 (1057 hom.)
• Consequence: FLNC NM_001458.5 intron
• Scores: Splicing: ADA: 0.0003501
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0410
• Publications: 2 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-AS1 (HGNC:53474): (FLNC antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 7-128851443-C-T is Benign according to our data. Variant chr7-128851443-C-T is described in ClinVar as Benign. ClinVar VariationId is 258149.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 = 0.0275 (4189/152324) while in subpopulation NFE AF = 0.0377 (2567/68028). AF 95% confidence interval is 0.0365. There are 93 homozygotes in GnomAd4. There are 2170 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4189 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.5669-12C>T		intron	N/A	NP_001449.3
	FLNC-AS1	NR_149055.1		n.273G>A		non_coding_transcript_exon	Exon 3 of 4
	FLNC	NM_001127487.2		c.5570-12C>T		intron	N/A	NP_001120959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.5669-12C>T		intron	N/A	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.5570-12C>T		intron	N/A	ENSP00000344002.6
	FLNC-AS1	ENST00000469965.1	TSL:4	n.273G>A		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4190 AN: 152206 Hom.: 93 Cov.: 33

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0308

Gnomad FIN AF: 0.0811

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.0312 AC: 7794 AN: 249420 AF XY: 0.0318

Gnomad AFR exome AF: 0.00594

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0204

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0765

Gnomad NFE exome AF: 0.0388

Gnomad OTH exome AF: 0.0278

GnomAD4 exome AF: 0.0343 AC: 50078 AN: 1461596 Hom.: 1057 Cov.: 34 AF XY: 0.0346 AC XY: 25148 AN XY: 727108

African (AFR) AF: 0.00469 AC: 157 AN: 33480

American (AMR) AF: 0.0106 AC: 475 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 502 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0311 AC: 2682 AN: 86258

European-Finnish (FIN) AF: 0.0710 AC: 3771 AN: 53144

Middle Eastern (MID) AF: 0.0149 AC: 86 AN: 5768

European-Non Finnish (NFE) AF: 0.0367 AC: 40775 AN: 1112000

Other (OTH) AF: 0.0269 AC: 1623 AN: 60386

GnomAD4 genome AF: 0.0275 AC: 4189 AN: 152324 Hom.: 93 Cov.: 33 AF XY: 0.0291 AC XY: 2170 AN XY: 74482

African (AFR) AF: 0.00642 AC: 267 AN: 41564

American (AMR) AF: 0.0146 AC: 223 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5194

South Asian (SAS) AF: 0.0309 AC: 149 AN: 4826

European-Finnish (FIN) AF: 0.0811 AC: 861 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0377 AC: 2567 AN: 68028

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.0318 Hom.: 16

Bravo AF: 0.0210

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

5669-12C>T in intron 34 of FLNC: This variant is not expected to have clinical s ignificance because it has been identified in 3.5% (300/8532) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs79790270).

Jul 29, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 13, 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.

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.4
DANN	Benign	0.74
PhyloP100		-0.041
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.030
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: rs79790270; hg19: chr7-128491497;