rs55907818

Positions:

• chr7-128837566-G-A

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.850+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0853 in 1,613,974 control chromosomes in the GnomAD database, including 6,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (515 hom., cov: 33)
  • Exomes 𝑓: 0.086 (5485 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.50

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=-0.91).
• BP6: Variant 7-128837566-G-A is Benign according to our data. Variant chr7-128837566-G-A is described in ClinVar as [Benign]. Clinvar id is 258154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128837566-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.086 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.850+18G>A		intron_variant		ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.850+18G>A		intron_variant			NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.850+18G>A		intron_variant		1	NM_001458.5	ENSP00000327145	P3
FLNC	ENST00000346177.6	c.850+18G>A		intron_variant		1		ENSP00000344002	A1

Frequencies

GnomAD3 genomes AF: 0.0808 AC: 12304 AN: 152192 Hom.: 517 Cov.: 33

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0504

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0870

Gnomad SAS AF: 0.0928

Gnomad FIN AF: 0.0629

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0873

Gnomad OTH AF: 0.0961

GnomAD3 exomes AF: 0.0789 AC: 19679 AN: 249328 Hom.: 825 AF XY: 0.0808 AC XY: 10935 AN XY: 135358

Gnomad AFR exome AF: 0.0838

Gnomad AMR exome AF: 0.0384

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0725

Gnomad SAS exome AF: 0.0872

Gnomad FIN exome AF: 0.0684

Gnomad NFE exome AF: 0.0882

Gnomad OTH exome AF: 0.0903

GnomAD4 exome AF: 0.0858 AC: 125360 AN: 1461664 Hom.: 5485 Cov.: 36 AF XY: 0.0862 AC XY: 62649 AN XY: 727148

Gnomad4 AFR exome AF: 0.0826

Gnomad4 AMR exome AF: 0.0420

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.0942

Gnomad4 SAS exome AF: 0.0879

Gnomad4 FIN exome AF: 0.0711

Gnomad4 NFE exome AF: 0.0874

Gnomad4 OTH exome AF: 0.0859

GnomAD4 genome AF: 0.0809 AC: 12315 AN: 152310 Hom.: 515 Cov.: 33 AF XY: 0.0792 AC XY: 5897 AN XY: 74480

Gnomad4 AFR AF: 0.0804

Gnomad4 AMR AF: 0.0502

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.0872

Gnomad4 SAS AF: 0.0931

Gnomad4 FIN AF: 0.0629

Gnomad4 NFE AF: 0.0873

Gnomad4 OTH AF: 0.0984

Alfa AF: 0.0880 Hom.: 155

Bravo AF: 0.0803

Asia WGS AF: 0.101 AC: 352 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 08, 2016	- -

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	-0.91
CADD	Benign	0.015
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: rs55907818; hg19: chr7-128477620; COSMIC: COSV57956389; COSMIC: COSV57956389;