7-128850499-T-C

Position:

• chr7-128850499-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000325888.13(FLNC):​c.5398+16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,598,528 control chromosomes in the GnomAD database, including 48,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (10268 hom., cov: 33)
  • Exomes 𝑓: 0.21 (38021 hom.)
• Consequence: FLNC ENST00000325888.13 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0790

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-128850499-T-C is Benign according to our data. Variant chr7-128850499-T-C is described in ClinVar as [Benign]. Clinvar id is 258148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128850499-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.5398+16T>C		intron_variant		ENST00000325888.13	NP_001449.3
FLNC-AS1	NR_149055.1	n.316-94A>G		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.5299+16T>C		intron_variant			NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.5398+16T>C		intron_variant		1	NM_001458.5	ENSP00000327145	P3
FLNC	ENST00000346177.6	c.5299+16T>C		intron_variant		1		ENSP00000344002	A1
FLNC-AS1	ENST00000469965.1	n.316-94A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48317 AN: 151982 Hom.: 10234 Cov.: 33

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.282

GnomAD3 exomes AF: 0.253 AC: 62899 AN: 248264 Hom.: 9771 AF XY: 0.247 AC XY: 33289 AN XY: 134738

Gnomad AFR exome AF: 0.604

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.459

Gnomad SAS exome AF: 0.288

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.193

Gnomad OTH exome AF: 0.230

GnomAD4 exome AF: 0.215 AC: 310440 AN: 1446428 Hom.: 38021 Cov.: 30 AF XY: 0.216 AC XY: 155333 AN XY: 720604

Gnomad4 AFR exome AF: 0.607

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.461

Gnomad4 SAS exome AF: 0.288

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.190

Gnomad4 OTH exome AF: 0.230

GnomAD4 genome AF: 0.318 AC: 48398 AN: 152100 Hom.: 10268 Cov.: 33 AF XY: 0.316 AC XY: 23516 AN XY: 74350

Gnomad4 AFR AF: 0.598

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.466

Gnomad4 SAS AF: 0.311

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.284

Alfa AF: 0.254 Hom.: 1353

Bravo AF: 0.332

Asia WGS AF: 0.403 AC: 1401 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.90
CADD	Benign	5.8
DANN	Benign	0.62

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: rs13227216; hg19: chr7-128490553; COSMIC: COSV57949951;