rs71581921

Positions:

• chr7-128842780-C-T

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.2390-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,612,962 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (11 hom., cov: 33)
  • Exomes 𝑓: 0.011 (115 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.189

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 7-128842780-C-T is Benign according to our data. Variant chr7-128842780-C-T is described in ClinVar as [Benign]. Clinvar id is 258137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128842780-C-T is described in Lovd as [Benign]. Variant chr7-128842780-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00811 (1236/152330) while in subpopulation NFE AF= 0.0106 (723/68014). AF 95% confidence interval is 0.00999. There are 11 homozygotes in gnomad4. There are 614 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1236 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.2390-14C>T		intron_variant		ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.2390-14C>T		intron_variant			NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.2390-14C>T		intron_variant		1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.2390-14C>T		intron_variant		1		ENSP00000344002.6
FLNC	ENST00000388853.3	n.506-14C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1236 AN: 152212 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00667

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0102 AC: 2507 AN: 246420 Hom.: 23 AF XY: 0.00979 AC XY: 1315 AN XY: 134268

Gnomad AFR exome AF: 0.00250

Gnomad AMR exome AF: 0.00682

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.0195

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0111 AC: 16205 AN: 1460632 Hom.: 115 Cov.: 38 AF XY: 0.0108 AC XY: 7871 AN XY: 726590

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.00701

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.0192

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.00916

GnomAD4 genome AF: 0.00811 AC: 1236 AN: 152330 Hom.: 11 Cov.: 33 AF XY: 0.00824 AC XY: 614 AN XY: 74482

Gnomad4 AFR AF: 0.00281

Gnomad4 AMR AF: 0.00666

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0184

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0103 Hom.: 2

Bravo AF: 0.00744

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	FLNC: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 22, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	10
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs71581921; hg19: chr7-128482834;