7-128849421-C-G

Position:

• chr7-128849421-C-G

Variant summary

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

The ENST00000325888.13(FLNC):​c.5042C>G​(p.Thr1681Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000424 in 1,614,200 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. T1681M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (4 hom.)
• Consequence: FLNC ENST00000325888.13 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.91

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 in gene, where missense usually causes diseases (based on misZ statistic), FLNC. . Gene score misZ 2.789 (greater than the threshold 3.09). Trascript score misZ 5.9457 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, heart conduction disease, familial isolated restrictive cardiomyopathy, hypertrophic cardiomyopathy 26, distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5.
• BP4: Computational evidence support a benign effect (MetaRNN=0.011175424).
• BP6: Variant 7-128849421-C-G is Benign according to our data. Variant chr7-128849421-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 196617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128849421-C-G is described in Lovd as [Benign]. Variant chr7-128849421-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00182 (277/152340) while in subpopulation AFR AF= 0.00563 (234/41576). AF 95% confidence interval is 0.00504. There are 0 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 277 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.5042C>G	p.Thr1681Arg	missense_variant	30/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.5042C>G	p.Thr1681Arg	missense_variant	30/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.5042C>G	p.Thr1681Arg	missense_variant	30/48	1	NM_001458.5	ENSP00000327145	P3
FLNC	ENST00000346177.6	c.5042C>G	p.Thr1681Arg	missense_variant	30/47	1		ENSP00000344002	A1

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 275 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000541 AC: 135 AN: 249518 Hom.: 0 AF XY: 0.000392 AC XY: 53 AN XY: 135330

Gnomad AFR exome AF: 0.00578

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000279 AC: 408 AN: 1461860 Hom.: 4 Cov.: 37 AF XY: 0.000243 AC XY: 177 AN XY: 727226

Gnomad4 AFR exome AF: 0.00756

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74494

Gnomad4 AFR AF: 0.00563

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000157 Hom.: 0

Bravo AF: 0.00213

ESP6500AA AF: 0.00411 AC: 18

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000569 AC: 69

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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	GeneDx	Jun 26, 2020	This variant is associated with the following publications: (PMID: 28356264) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FLNC: BS1, BS2 -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 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

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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.054	D
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.53	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.59	T;T
Polyphen		0.90	P;P
Vest4		0.46
MVP		0.43
MPC		0.41
ClinPred		0.013	T
GERP RS		4.5
Varity_R		0.25
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs193159707; hg19: chr7-128489475;