rs146953558

chr7-128845186-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):c.3721C>T(p.Arg1241Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00865 in 1,613,962 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1241H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0069 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (67 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.819

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNC
• BP4: Computational evidence support a benign effect (MetaRNN=0.0095562935).
• BP6: Variant 7-128845186-C-T is Benign according to our data. Variant chr7-128845186-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128845186-C-T is described in Lovd as [Benign]. Variant chr7-128845186-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00693 (1055/152346) while in subpopulation NFE AF= 0.0111 (752/68038). AF 95% confidence interval is 0.0104. There are 11 homozygotes in gnomad4. There are 544 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1056 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.3721C>T	p.Arg1241Cys	missense_variant	21/48	ENST00000325888.13
FLNC	NM_001127487.2	c.3721C>T	p.Arg1241Cys	missense_variant	21/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.3721C>T	p.Arg1241Cys	missense_variant	21/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.3721C>T	p.Arg1241Cys	missense_variant	21/47	1		A1

Frequencies

GnomAD3 genomes AF: 0.00694 AC: 1056 AN: 152228 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00597 AC: 1479 AN: 247646 Hom.: 13 AF XY: 0.00619 AC XY: 833 AN XY: 134574

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.00942

Gnomad OTH exome AF: 0.00512

GnomAD4 exome AF: 0.00883 AC: 12901 AN: 1461616 Hom.: 67 Cov.: 34 AF XY: 0.00865 AC XY: 6290 AN XY: 727130

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.00218

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00662

GnomAD4 genome AF: 0.00693 AC: 1055 AN: 152346 Hom.: 11 Cov.: 32 AF XY: 0.00730 AC XY: 544 AN XY: 74502

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0133

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00851 Hom.: 11

Bravo AF: 0.00589

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00115 AC: 5

ESP6500EA AF: 0.00951 AC: 81

ExAC AF: 0.00624 AC: 756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 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	Genetic Services Laboratory, University of Chicago	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2015	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FLNC: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 16, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2018

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0096	T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.56
Sift	Benign	0.037	D;D
Sift4G	Benign	0.061	T;T
Polyphen		0.10	B;D
Vest4		0.60
MVP		0.66
MPC		1.1
ClinPred		0.019	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.18
gMVP		0.59

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: rs146953558; hg19: chr7-128485240; COSMIC: COSV57966247; COSMIC: COSV57966247;