rs1136956

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004924.6(ACTN4):c.2563T>C(p.Leu855Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,612,768 control chromosomes in the GnomAD database, including 46,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3686 hom., cov: 30)

Exomes 𝑓: 0.24 ( 43229 hom. )

Consequence

ACTN4
NM_004924.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.25

Publications

24 publications found

Variant links:

Genes affected

ACTN4 (HGNC:166): (actinin alpha 4) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis. [provided by RefSeq, Jul 2008]

ACTN4 Gene-Disease associations (from GenCC):

focal segmental glomerulosclerosis 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACTN4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 19-38729140-T-C is Benign according to our data. Variant chr19-38729140-T-C is described in ClinVar as Benign. ClinVar VariationId is 259576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.25 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6 link	c.2563T>C	p.Leu855Leu	synonymous_variant	Exon 20 of 21	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7 link	c.2563T>C	p.Leu855Leu	synonymous_variant	Exon 20 of 21	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

31784

AN:

151702

Hom.:

3686

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.361

Gnomad AMR

AF:

0.222

Gnomad ASJ

AF:

0.275

Gnomad EAS

AF:

0.0540

Gnomad SAS

AF:

0.259

Gnomad FIN

AF:

0.186

Gnomad MID

AF:

0.421

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.242

GnomAD2 exomes

AF:

0.222

AC:

55596

AN:

250552

AF XY:

0.229

show subpopulations

Gnomad AFR exome

AF:

0.136

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.278

Gnomad EAS exome

AF:

0.0444

Gnomad FIN exome

AF:

0.194

Gnomad NFE exome

AF:

0.262

Gnomad OTH exome

AF:

0.264

GnomAD4 exome

AF:

0.238

AC:

348309

AN:

1460948

Hom.:

43229

Cov.:

AF XY:

0.241

AC XY:

175116

AN XY:

726774

show subpopulations

African (AFR)

AF:

0.139

AC:

4640

AN:

33480

American (AMR)

AF:

0.186

AC:

8301

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

7319

AN:

26136

East Asian (EAS)

AF:

0.0481

AC:

1908

AN:

39700

South Asian (SAS)

AF:

0.267

AC:

23059

AN:

86256

European-Finnish (FIN)

AF:

0.194

AC:

10183

AN:

52504

Middle Eastern (MID)

AF:

0.394

AC:

2271

AN:

5768

European-Non Finnish (NFE)

AF:

0.249

AC:

276454

AN:

1111994

Other (OTH)

AF:

0.235

AC:

14174

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

18555

37109

55664

74218

92773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9126

18252

27378

36504

45630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.209

AC:

31798

AN:

151820

Hom.:

3686

Cov.:

AF XY:

0.207

AC XY:

15368

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.136

AC:

5647

AN:

41396

American (AMR)

AF:

0.222

AC:

3390

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.275

AC:

952

AN:

3466

East Asian (EAS)

AF:

0.0541

AC:

279

AN:

5154

South Asian (SAS)

AF:

0.257

AC:

1232

AN:

4786

European-Finnish (FIN)

AF:

0.186

AC:

1964

AN:

10558

Middle Eastern (MID)

AF:

0.442

AC:

130

AN:

294

European-Non Finnish (NFE)

AF:

0.256

AC:

17366

AN:

67882

Other (OTH)

AF:

0.242

AC:

509

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1239

2479

3718

4958

6197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

332

664

996

1328

1660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.240

Hom.:

2310

Bravo

AF:

0.208

Asia WGS

AF:

0.178

AC:

621

AN:

3478

EpiCase

AF:

0.278

EpiControl

AF:

0.277

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 40% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 37. Only high quality variants are reported. -

Focal segmental glomerulosclerosis 1

Benign:2

Apr 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

7.3

(source)

DANN

Benign

0.85

PhyloP100

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over