7-128858466-T-C

Position:

• chr7-128858466-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001458.5(FLNC):​c.8121T>C​(p.Ile2707Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,608,118 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (110 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.09

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:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 7-128858466-T-C is Benign according to our data. Variant chr7-128858466-T-C is described in ClinVar as [Benign]. Clinvar id is 129101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128858466-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0158 (2396/151972) while in subpopulation AFR AF= 0.0471 (1946/41354). AF 95% confidence interval is 0.0453. There are 48 homozygotes in gnomad4. There are 1132 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2396 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.8121T>C	p.Ile2707Ile	synonymous_variant	48/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.8022T>C	p.Ile2674Ile	synonymous_variant	47/47		NP_001120959.1
FLNC-AS1	NR_149055.1	n.102+4059A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.8121T>C	p.Ile2707Ile	synonymous_variant	48/48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.8022T>C	p.Ile2674Ile	synonymous_variant	47/47	1		ENSP00000344002.6
FLNC-AS1	ENST00000469965.1	n.102+4059A>G		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2392 AN: 151854 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0471

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.0279

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00933 AC: 2329 AN: 249500 Hom.: 60 AF XY: 0.00973 AC XY: 1317 AN XY: 135366

Gnomad AFR exome AF: 0.0483

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0120

Gnomad SAS exome AF: 0.0343

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00163

Gnomad OTH exome AF: 0.00660

GnomAD4 exome AF: 0.00312 AC: 4541 AN: 1456146 Hom.: 110 Cov.: 32 AF XY: 0.00368 AC XY: 2667 AN XY: 724240

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.00231

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0166

Gnomad4 SAS exome AF: 0.0210

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000740

Gnomad4 OTH exome AF: 0.00443

GnomAD4 genome AF: 0.0158 AC: 2396 AN: 151972 Hom.: 48 Cov.: 32 AF XY: 0.0152 AC XY: 1132 AN XY: 74280

Gnomad4 AFR AF: 0.0471

Gnomad4 AMR AF: 0.00511

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0153

Gnomad4 SAS AF: 0.0279

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00536 Hom.: 7

Bravo AF: 0.0170

EpiCase AF: 0.00202

EpiControl AF: 0.00213

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 14, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 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	GeneDx	Aug 26, 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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.97
DANN	Benign	0.46

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: rs28437296; hg19: chr7-128498520; COSMIC: COSV99972436; COSMIC: COSV99972436;