7-128842214-T-C

Variant summary

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

The NM_001458.5(FLNC):c.2122-17T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,613,312 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (167 hom.)
• Consequence: FLNC NM_001458.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0540

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-128842214-T-C is Benign according to our data. Variant chr7-128842214-T-C is described in ClinVar as [Benign]. Clinvar id is 258130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128842214-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.2122-17T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000325888.13
FLNC	NM_001127487.2	c.2122-17T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.2122-17T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.2122-17T>C		splice_polypyrimidine_tract_variant, intron_variant		1		A1
FLNC	ENST00000388853.3	n.238-17T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 523 AN: 152180 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.0579

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00824 AC: 2040 AN: 247426 Hom.: 62 AF XY: 0.00996 AC XY: 1342 AN XY: 134690

Gnomad AFR exome AF: 0.000456

Gnomad AMR exome AF: 0.000873

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0173

Gnomad SAS exome AF: 0.0502

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00416

GnomAD4 exome AF: 0.00507 AC: 7401 AN: 1461014 Hom.: 167 Cov.: 33 AF XY: 0.00629 AC XY: 4572 AN XY: 726790

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0189

Gnomad4 SAS exome AF: 0.0499

Gnomad4 FIN exome AF: 0.0000378

Gnomad4 NFE exome AF: 0.00172

Gnomad4 OTH exome AF: 0.00623

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152298 Hom.: 12 Cov.: 33 AF XY: 0.00462 AC XY: 344 AN XY: 74454

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0205

Gnomad4 SAS AF: 0.0571

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00171

Asia WGS AF: 0.0390 AC: 137 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.7
Dann	Benign	0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs144828462; hg19: chr7-128482268;