rs201905890

chr7-128840598-G-Achr7-128840598-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001458.5(FLNC):c.1600G>A(p.Glu534Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000841 in 1,614,218 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E534Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (3 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 4.23

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 -10 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FLNC
• BP4: Computational evidence support a benign effect (MetaRNN=0.07272342).
• BP6: Variant 7-128840598-G-A is Benign according to our data. Variant chr7-128840598-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193631.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=5, Uncertain_significance=1}. Variant chr7-128840598-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000788 (120/152336) while in subpopulation NFE AF= 0.00138 (94/68024). AF 95% confidence interval is 0.00116. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 120 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.1600G>A	p.Glu534Lys	missense_variant	10/48	ENST00000325888.13
FLNC	NM_001127487.2	c.1600G>A	p.Glu534Lys	missense_variant	10/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.1600G>A	p.Glu534Lys	missense_variant	10/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.1600G>A	p.Glu534Lys	missense_variant	10/47	1		A1

Frequencies

GnomAD3 genomes AF: 0.000788 AC: 120 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000785 AC: 196 AN: 249574 Hom.: 0 AF XY: 0.000783 AC XY: 106 AN XY: 135408

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000847 AC: 1238 AN: 1461882 Hom.: 3 Cov.: 33 AF XY: 0.000850 AC XY: 618 AN XY: 727240

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00169

Gnomad4 NFE exome AF: 0.000965

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000792 AC XY: 59 AN XY: 74488

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00119 Hom.: 1

Bravo AF: 0.000589

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000463 AC: 2

ESP6500EA AF: 0.00106 AC: 9

ExAC AF: 0.000808 AC: 98

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	FLNC: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2019	This variant is associated with the following publications: (PMID: 27296017, 28008999) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 03, 2017

- -

FLNC-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

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

May 16, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 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	0.26
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.19
Sift	Benign	0.70	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.028	B;B
Vest4		0.77
MVP		0.55
MPC		0.33
ClinPred		0.032	T
GERP RS		3.4
Varity_R		0.10
gMVP		0.68

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: rs201905890; hg19: chr7-128480652; COSMIC: COSV99064146; COSMIC: COSV99064146;