rs192725607

chr7-128842234-G-A

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.2125G>A(p.Ala709Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000595 in 1,613,610 control chromosomes in the GnomAD database, including 4 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. A709S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (4 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.73

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=0.009004623).
• BP6: Variant 7-128842234-G-A is Benign according to our data. Variant chr7-128842234-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128842234-G-A is described in Lovd as [Likely_benign]. Variant chr7-128842234-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000519 (79/152330) while in subpopulation AMR AF= 0.000915 (14/15308). AF 95% confidence interval is 0.000572. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.2125G>A	p.Ala709Thr	missense_variant	14/48	ENST00000325888.13
FLNC	NM_001127487.2	c.2125G>A	p.Ala709Thr	missense_variant	14/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.2125G>A	p.Ala709Thr	missense_variant	14/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.2125G>A	p.Ala709Thr	missense_variant	14/47	1		A1
FLNC	ENST00000388853.3	n.241G>A		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00108 AC: 269 AN: 248350 Hom.: 1 AF XY: 0.000992 AC XY: 134 AN XY: 135036

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.00479

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00103

Gnomad NFE exome AF: 0.000685

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000603 AC: 881 AN: 1461280 Hom.: 4 Cov.: 33 AF XY: 0.000601 AC XY: 437 AN XY: 726936

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00132

Gnomad4 NFE exome AF: 0.000533

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000577 AC XY: 43 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000573 Hom.: 0

Bravo AF: 0.000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.00102 AC: 123

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	FLNC: BS1 -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.0090	T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.27
Sift	Benign	0.11	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.95	P;D
Vest4		0.52
MVP		0.46
MPC		0.74
ClinPred		0.069	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs192725607; hg19: chr7-128482288;