rs201149834

Variant names:

• chr7-128857346-A-G
• rs201149834
• NM_001458.5:c.7780+10A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):​c.7780+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,599,408 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.69

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-128857346-A-G is Benign according to our data. Variant chr7-128857346-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128857346-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.004 (608/152056) while in subpopulation AFR AF= 0.0102 (422/41418). AF 95% confidence interval is 0.00939. There are 1 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 608 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.7780+10A>G		intron_variant	Intron 46 of 47	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.7681+10A>G		intron_variant	Intron 45 of 46		NP_001120959.1
FLNC-AS1	NR_149055.1	n.103-3949T>C		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.7780+10A>G		intron_variant	Intron 46 of 47	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.7681+10A>G		intron_variant	Intron 45 of 46	1		ENSP00000344002.6
FLNC-AS1	ENST00000469965.1	n.103-3949T>C		intron_variant	Intron 1 of 3	4

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 607 AN: 151938 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00281 AC: 685 AN: 243776 Hom.: 1 AF XY: 0.00240 AC XY: 319 AN XY: 132712

Gnomad AFR exome AF: 0.00969

Gnomad AMR exome AF: 0.00624

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00213

Gnomad SAS exome AF: 0.000821

Gnomad FIN exome AF: 0.00114

Gnomad NFE exome AF: 0.00203

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00184 AC: 2656 AN: 1447352 Hom.: 4 Cov.: 31 AF XY: 0.00170 AC XY: 1228 AN XY: 720652

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.00549

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00661

Gnomad4 SAS exome AF: 0.000732

Gnomad4 FIN exome AF: 0.00117

Gnomad4 NFE exome AF: 0.00138

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00400 AC: 608 AN: 152056 Hom.: 1 Cov.: 33 AF XY: 0.00378 AC XY: 281 AN XY: 74342

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00249 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

May 19, 2017

GeneDx

Significance: Likely 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. -

-

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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

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

- -

Aug 19, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FLNC: BS1 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiomyopathy Benign:1

Jan 31, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.17
DANN	Benign	0.45

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: rs201149834; hg19: chr7-128497400;