rs181067717

chr7-128851270-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.5578C>T(p.Arg1860Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00811 in 1,614,026 control chromosomes in the GnomAD database, including 62 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. R1860H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0084 (60 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 2.34

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.

• PP2: Missense variant where missense usually causes diseases, FLNC
• BP4: Computational evidence support a benign effect (MetaRNN=0.0066719353).
• BP6: Variant 7-128851270-C-T is Benign according to our data. Variant chr7-128851270-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 196888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128851270-C-T is described in Lovd as [Likely_benign]. Variant chr7-128851270-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00522 (795/152272) while in subpopulation AMR AF= 0.00961 (147/15298). AF 95% confidence interval is 0.00834. There are 2 homozygotes in gnomad4. There are 359 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 794 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.5578C>T	p.Arg1860Cys	missense_variant	34/48	ENST00000325888.13
FLNC-AS1	NR_149055.1	n.315+131G>A		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.5479C>T	p.Arg1827Cys	missense_variant	33/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.5578C>T	p.Arg1860Cys	missense_variant	34/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.5479C>T	p.Arg1827Cys	missense_variant	33/47	1		A1
FLNC-AS1	ENST00000469965.1	n.315+131G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 794 AN: 152154 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00806

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00536 AC: 1336 AN: 249482 Hom.: 9 AF XY: 0.00564 AC XY: 763 AN XY: 135374

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.00571

Gnomad ASJ exome AF: 0.00725

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.00843

Gnomad OTH exome AF: 0.00561

GnomAD4 exome AF: 0.00842 AC: 12302 AN: 1461754 Hom.: 60 Cov.: 33 AF XY: 0.00815 AC XY: 5928 AN XY: 727184

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00552

Gnomad4 ASJ exome AF: 0.00742

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.00154

Gnomad4 NFE exome AF: 0.00999

Gnomad4 OTH exome AF: 0.00790

GnomAD4 genome AF: 0.00522 AC: 795 AN: 152272 Hom.: 2 Cov.: 33 AF XY: 0.00482 AC XY: 359 AN XY: 74464

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00806

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00724 Hom.: 8

Bravo AF: 0.00536

ESP6500AA AF: 0.00124 AC: 5

ESP6500EA AF: 0.00621 AC: 52

ExAC AF: 0.00534 AC: 646

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00812

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 30, 2023	- -
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	Genetic Services Laboratory, University of Chicago	May 06, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 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. -

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 07, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FLNC: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

FLNC-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 04, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

This alteration is classified as likely 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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.96	D;D
Vest4		0.40
MVP		0.31
MPC		1.9
ClinPred		0.028	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.26
gMVP		0.75

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: rs181067717; hg19: chr7-128491324;