rs181134489

Variant names:

• chr7-128840175-C-A
• rs181134489
• NM_001458.5:c.1549+15C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-128840175-C-A
• chr7-128840175-C-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.1549+15C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 1,613,320 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (42 hom.)
• Consequence: FLNC NM_001458.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.246
• Publications: 0 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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics, G2P
• myofibrillar myopathy 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
• hypertrophic cardiomyopathy 26

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• distal myopathy with posterior leg and anterior hand involvement

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-128840175-C-A is Benign according to our data. Variant chr7-128840175-C-A is described in ClinVar as Benign. ClinVar VariationId is 258126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00392 (597/152256) while in subpopulation NFE AF = 0.0067 (456/68010). AF 95% confidence interval is 0.0062. There are 4 homozygotes in GnomAd4. There are 256 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 597 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	NM_001458.5	MANE Select	c.1549+15C>A		intron	N/A	NP_001449.3
	FLNC	NM_001127487.2		c.1549+15C>A		intron	N/A	NP_001120959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLNC	ENST00000325888.13	TSL:1 MANE Select	c.1549+15C>A		intron	N/A	ENSP00000327145.8
	FLNC	ENST00000346177.6	TSL:1	c.1549+15C>A		intron	N/A	ENSP00000344002.6
	FLNC	ENST00000714183.1		c.1549+15C>A		intron	N/A	ENSP00000519472.1

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 597 AN: 152138 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00669

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00424 AC: 1053 AN: 248388 AF XY: 0.00428

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00446

Gnomad ASJ exome AF: 0.00747

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000907

Gnomad NFE exome AF: 0.00652

Gnomad OTH exome AF: 0.00579

GnomAD4 exome AF: 0.00624 AC: 9111 AN: 1461064 Hom.: 42 Cov.: 32 AF XY: 0.00604 AC XY: 4388 AN XY: 726798

African (AFR) AF: 0.00137 AC: 46 AN: 33478

American (AMR) AF: 0.00427 AC: 191 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00742 AC: 194 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86256

European-Finnish (FIN) AF: 0.00110 AC: 58 AN: 52670

Middle Eastern (MID) AF: 0.0180 AC: 104 AN: 5766

European-Non Finnish (NFE) AF: 0.00734 AC: 8165 AN: 1111956

Other (OTH) AF: 0.00522 AC: 315 AN: 60388

GnomAD4 genome AF: 0.00392 AC: 597 AN: 152256 Hom.: 4 Cov.: 33 AF XY: 0.00344 AC XY: 256 AN XY: 74444

African (AFR) AF: 0.000963 AC: 40 AN: 41554

American (AMR) AF: 0.00333 AC: 51 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00670 AC: 456 AN: 68010

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00533 Hom.: 1

Bravo AF: 0.00433

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	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	-0.80
CADD	Benign	16
DANN	Benign	0.50
PhyloP100		-0.25
Mutation Taster		=100/0	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: rs181134489; hg19: chr7-128480229; COSMIC: COSV57957045; COSMIC: COSV57957045;