7-128850499-T-C

Variant names:

• chr7-128850499-T-C
• rs13227216
• NM_001458.5:c.5398+16T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001458.5(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 NM_001458.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0790
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 258148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001458.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.5398+16T>C		intron	N/A	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.5299+16T>C		intron	N/A	NP_001120959.1	Q14315-2
	FLNC-AS1	NR_149055.1		n.316-94A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.5398+16T>C		intron	N/A	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.5299+16T>C		intron	N/A	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.5296+16T>C		intron	N/A	ENSP00000620322.1

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

GnomAD2 exomes AF: 0.253 AC: 62899 AN: 248264 AF XY: 0.247

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 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

African (AFR) AF: 0.607 AC: 20207 AN: 33286

American (AMR) AF: 0.223 AC: 9973 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3836 AN: 26054

East Asian (EAS) AF: 0.461 AC: 18283 AN: 39656

South Asian (SAS) AF: 0.288 AC: 24724 AN: 85940

European-Finnish (FIN) AF: 0.198 AC: 10528 AN: 53170

Middle Eastern (MID) AF: 0.155 AC: 769 AN: 4946

European-Non Finnish (NFE) AF: 0.190 AC: 208324 AN: 1098782

Other (OTH) AF: 0.230 AC: 13796 AN: 59884

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

African (AFR) AF: 0.598 AC: 24800 AN: 41484

American (AMR) AF: 0.209 AC: 3204 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 545 AN: 3464

East Asian (EAS) AF: 0.466 AC: 2403 AN: 5154

South Asian (SAS) AF: 0.311 AC: 1498 AN: 4814

European-Finnish (FIN) AF: 0.196 AC: 2076 AN: 10590

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13156 AN: 67990

Other (OTH) AF: 0.284 AC: 596 AN: 2102

Alfa AF: 0.262 Hom.: 1487

Bravo AF: 0.332

Asia WGS AF: 0.403 AC: 1401 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.8
DANN	Benign	0.62
PhyloP100		-0.079
Mutation Taster		=33/67	disease causing

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

Other links and lift over

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