rs58914363

Variant names:

• chr7-128851552-G-A
• rs58914363
• NM_001458.5:c.5766G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-128851552-G-A
• chr7-128851552-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001458.5(FLNC):​c.5766G>A​(p.Ala1922Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,613,974 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1922A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00083 (4 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -5.04
• Publications: 1 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 7-128851552-G-A is Benign according to our data. Variant chr7-128851552-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00102 (155/152328) while in subpopulation AMR AF = 0.00209 (32/15306). AF 95% confidence interval is 0.00152. There are 1 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 155 AD gene.

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.5766G>A	p.Ala1922Ala	synonymous	Exon 35 of 48	NP_001449.3	Q14315-1
	FLNC	NM_001127487.2		c.5667G>A	p.Ala1889Ala	synonymous	Exon 34 of 47	NP_001120959.1	Q14315-2
	FLNC-AS1	NR_149055.1		n.216-52C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.5766G>A	p.Ala1922Ala	synonymous	Exon 35 of 48	ENSP00000327145.8	Q14315-1
	FLNC	ENST00000346177.6	TSL:1	c.5667G>A	p.Ala1889Ala	synonymous	Exon 34 of 47	ENSP00000344002.6	Q14315-2
	FLNC	ENST00000950263.1		c.5664G>A	p.Ala1888Ala	synonymous	Exon 34 of 47	ENSP00000620322.1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152210 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000908 AC: 228 AN: 251000 AF XY: 0.000943

Gnomad AFR exome AF: 0.000747

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000879

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000832 AC: 1216 AN: 1461646 Hom.: 4 Cov.: 34 AF XY: 0.000866 AC XY: 630 AN XY: 727130

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00136 AC: 61 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86258

European-Finnish (FIN) AF: 0.000997 AC: 53 AN: 53182

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.000818 AC: 910 AN: 1112008

Other (OTH) AF: 0.00119 AC: 72 AN: 60390

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.000980 AC XY: 73 AN XY: 74488

African (AFR) AF: 0.000818 AC: 34 AN: 41570

American (AMR) AF: 0.00209 AC: 32 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000980 Hom.: 0

Bravo AF: 0.00122

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00190

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	1	Cardiomyopathy (1)
-	-	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	-0.90
CADD	Benign	0.025
DANN	Benign	0.71
PhyloP100		-5.0
Mutation Taster		=80/20	polymorphism

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: rs58914363; hg19: chr7-128491606; COSMIC: COSV100368942;