7-128851549-T-C

Variant names:

• chr7-128851549-T-C
• rs3816884
• NM_001458.5:c.5763T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001458.5(FLNC):​c.5763T>C​(p.Thr1921Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0813 in 1,613,870 control chromosomes in the GnomAD database, including 14,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1921T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (5273 hom., cov: 33)
  • Exomes 𝑓: 0.071 (9457 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -6.58
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 7-128851549-T-C is Benign according to our data. Variant chr7-128851549-T-C is described in ClinVar as Benign. ClinVar VariationId is 129094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.465 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.5763T>C	p.Thr1921Thr	synonymous	Exon 35 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.5664T>C	p.Thr1888Thr	synonymous	Exon 34 of 47	NP_001120959.1	Q14315-2
	FLNC-AS1	NR_149055.1		n.216-49A>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.5763T>C	p.Thr1921Thr	synonymous	Exon 35 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.5664T>C	p.Thr1888Thr	synonymous	Exon 34 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.5661T>C	p.Thr1887Thr	synonymous	Exon 34 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27646 AN: 152124 Hom.: 5263 Cov.: 33

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0428

Gnomad OTH AF: 0.139

GnomAD2 exomes AF: 0.125 AC: 31322 AN: 250952 AF XY: 0.116

Gnomad AFR exome AF: 0.473

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.0183

Gnomad EAS exome AF: 0.361

Gnomad FIN exome AF: 0.0265

Gnomad NFE exome AF: 0.0439

Gnomad OTH exome AF: 0.0910

GnomAD4 exome AF: 0.0709 AC: 103562 AN: 1461628 Hom.: 9457 Cov.: 34 AF XY: 0.0720 AC XY: 52344 AN XY: 727134

African (AFR) AF: 0.478 AC: 16006 AN: 33480

American (AMR) AF: 0.161 AC: 7184 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 477 AN: 26136

East Asian (EAS) AF: 0.334 AC: 13250 AN: 39700

South Asian (SAS) AF: 0.167 AC: 14424 AN: 86258

European-Finnish (FIN) AF: 0.0276 AC: 1467 AN: 53176

Middle Eastern (MID) AF: 0.0531 AC: 306 AN: 5768

European-Non Finnish (NFE) AF: 0.0403 AC: 44865 AN: 1111996

Other (OTH) AF: 0.0924 AC: 5583 AN: 60390

GnomAD4 genome AF: 0.182 AC: 27684 AN: 152242 Hom.: 5273 Cov.: 33 AF XY: 0.181 AC XY: 13449 AN XY: 74458

African (AFR) AF: 0.470 AC: 19512 AN: 41506

American (AMR) AF: 0.128 AC: 1964 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3468

East Asian (EAS) AF: 0.351 AC: 1815 AN: 5166

South Asian (SAS) AF: 0.183 AC: 884 AN: 4828

European-Finnish (FIN) AF: 0.0214 AC: 228 AN: 10630

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0428 AC: 2914 AN: 68022

Other (OTH) AF: 0.139 AC: 293 AN: 2112

Alfa AF: 0.0766 Hom.: 2530

Bravo AF: 0.203

Asia WGS AF: 0.272 AC: 943 AN: 3478

EpiCase AF: 0.0402

EpiControl AF: 0.0443

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.038
DANN	Benign	0.37
PhyloP100		-6.6
Mutation Taster		=80/20	polymorphism (auto)

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: rs3816884; hg19: chr7-128491603; COSMIC: COSV57957802;