chr19-38706105-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004924.6(ACTN4):c.546C>T(p.Asn182Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,613,490 control chromosomes in the GnomAD database, including 169,091 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12552 hom., cov: 32)

Exomes 𝑓: 0.46 ( 156539 hom. )

Consequence

ACTN4
NM_004924.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.54

Publications

30 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:

ENSG00000298338 (HGNC:):

ENSG00000298338 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 19-38706105-C-T is Benign according to our data. Variant chr19-38706105-C-T is described in ClinVar as Benign. ClinVar VariationId is 259582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.54 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6 link	c.546C>T	p.Asn182Asn	synonymous_variant	Exon 5 of 21	ENST00000252699.7	NP_004915.2	O43707-1A0A0S2Z3G9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7 link	c.546C>T	p.Asn182Asn	synonymous_variant	Exon 5 of 21	1	NM_004924.6	ENSP00000252699.2		O43707-1

Frequencies

GnomAD3 genomes

AF:

0.392

AC:

59575

AN:

151960

Hom.:

12559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.253

Gnomad AMI

AF:

0.519

Gnomad AMR

AF:

0.347

Gnomad ASJ

AF:

0.408

Gnomad EAS

AF:

0.436

Gnomad SAS

AF:

0.377

Gnomad FIN

AF:

0.499

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.466

Gnomad OTH

AF:

0.374

GnomAD2 exomes

AF:

0.411

AC:

103224

AN:

251394

AF XY:

0.418

show subpopulations

Gnomad AFR exome

AF:

0.249

Gnomad AMR exome

AF:

0.282

Gnomad ASJ exome

AF:

0.398

Gnomad EAS exome

AF:

0.431

Gnomad FIN exome

AF:

0.480

Gnomad NFE exome

AF:

0.463

Gnomad OTH exome

AF:

0.399

GnomAD4 exome

AF:

0.458

AC:

669353

AN:

1461412

Hom.:

156539

Cov.:

AF XY:

0.456

AC XY:

331326

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.238

AC:

7973

AN:

33472

American (AMR)

AF:

0.286

AC:

12781

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.395

AC:

10327

AN:

26130

East Asian (EAS)

AF:

0.521

AC:

20671

AN:

39692

South Asian (SAS)

AF:

0.397

AC:

34247

AN:

86252

European-Finnish (FIN)

AF:

0.479

AC:

25569

AN:

53404

Middle Eastern (MID)

AF:

0.286

AC:

1647

AN:

5766

European-Non Finnish (NFE)

AF:

0.477

AC:

529735

AN:

1111610

Other (OTH)

AF:

0.437

AC:

26403

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

20206

40412

60618

80824

101030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15646

31292

46938

62584

78230

<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:

0.392

AC:

59568

AN:

152078

Hom.:

12552

Cov.:

AF XY:

0.391

AC XY:

29086

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.253

AC:

10494

AN:

41478

American (AMR)

AF:

0.346

AC:

5293

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.408

AC:

1414

AN:

3468

East Asian (EAS)

AF:

0.436

AC:

2250

AN:

5160

South Asian (SAS)

AF:

0.377

AC:

1821

AN:

4826

European-Finnish (FIN)

AF:

0.499

AC:

5282

AN:

10584

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.466

AC:

31698

AN:

67962

Other (OTH)

AF:

0.370

AC:

780

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1779

3557

5336

7114

8893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<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:

0.437

Hom.:

14198

Bravo

AF:

0.372

Asia WGS

AF:

0.341

AC:

1188

AN:

3476

EpiCase

AF:

0.437

EpiControl

AF:

0.442

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Focal segmental glomerulosclerosis 1

Benign:4

Apr 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

not specified

Benign:3

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 46% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 43. Only high quality variants are reported. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.27

CADD

Benign

0.71

(source)

DANN

Benign

0.67

PhyloP100

-2.5

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

Splicevardb

2.0

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