rs116974302

chr7-128852943-C-T

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.6120C>T(p.Asp2040=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,613,570 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.63

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 7-128852943-C-T is Benign according to our data. Variant chr7-128852943-C-T is described in ClinVar as [Benign]. Clinvar id is 383328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128852943-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000624 (95/152270) while in subpopulation EAS AF= 0.016 (83/5176). AF 95% confidence interval is 0.0133. There are 1 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.6120C>T	p.Asp2040=	synonymous_variant	37/48	ENST00000325888.13
FLNC-AS1	NR_149055.1	n.215+342G>A		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.6021C>T	p.Asp2007=	synonymous_variant	36/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.6120C>T	p.Asp2040=	synonymous_variant	37/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.6021C>T	p.Asp2007=	synonymous_variant	36/47	1		A1
FLNC-AS1	ENST00000469965.1	n.215+342G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152152 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00132 AC: 329 AN: 249350 Hom.: 1 AF XY: 0.00118 AC XY: 160 AN XY: 135360

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0164

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000535 AC: 782 AN: 1461300 Hom.: 7 Cov.: 33 AF XY: 0.000541 AC XY: 393 AN XY: 726956

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0152

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152270 Hom.: 1 Cov.: 33 AF XY: 0.000833 AC XY: 62 AN XY: 74450

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0160

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.000922

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 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	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 09, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2019

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

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	3.5
Dann	Benign	0.87

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: rs116974302; hg19: chr7-128492997; COSMIC: COSV57950937;