rs117577125

Positions:

• chr7-128842204-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):​c.2122-27T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,612,762 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (29 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.19

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-128842204-T-C is Benign according to our data. Variant chr7-128842204-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 258131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128842204-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00349 (531/152262) while in subpopulation NFE AF= 0.00638 (434/68010). AF 95% confidence interval is 0.00589. There are 3 homozygotes in gnomad4. There are 231 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 531 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5	c.2122-27T>C		intron_variant		ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.2122-27T>C		intron_variant			NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.2122-27T>C		intron_variant		1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.2122-27T>C		intron_variant		1		ENSP00000344002.6
FLNC	ENST00000388853.3	n.238-27T>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 531 AN: 152144 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00638

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00340 AC: 836 AN: 246222 Hom.: 2 AF XY: 0.00350 AC XY: 470 AN XY: 134122

Gnomad AFR exome AF: 0.000720

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00158

Gnomad FIN exome AF: 0.00132

Gnomad NFE exome AF: 0.00615

Gnomad OTH exome AF: 0.00367

GnomAD4 exome AF: 0.00506 AC: 7385 AN: 1460500 Hom.: 29 Cov.: 33 AF XY: 0.00501 AC XY: 3640 AN XY: 726504

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00159

Gnomad4 FIN exome AF: 0.00127

Gnomad4 NFE exome AF: 0.00612

Gnomad4 OTH exome AF: 0.00454

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152262 Hom.: 3 Cov.: 33 AF XY: 0.00310 AC XY: 231 AN XY: 74436

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00638

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00323 Hom.: 0

Bravo AF: 0.00329

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.25
DANN	Benign	0.21
BranchPoint Hunter		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs117577125; hg19: chr7-128482258;