rs1136956

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 259576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38729140-T-C is described in Lovd as [Benign].

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	O43707-1A0A0S2Z3G9

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		O43707-1

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

GnomAD3 exomes

AF:

0.222

AC:

55596

AN:

250552

Hom.:

6884

AF XY:

0.229

AC XY:

31137

AN XY:

135766

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 SAS exome

AF:

0.269

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

Gnomad4 AFR exome

AF:

0.139

Gnomad4 AMR exome

AF:

0.186

Gnomad4 ASJ exome

AF:

0.280

Gnomad4 EAS exome

AF:

0.0481

Gnomad4 SAS exome

AF:

0.267

Gnomad4 FIN exome

AF:

0.194

Gnomad4 NFE exome

AF:

0.249

Gnomad4 OTH exome

AF:

0.235

GnomAD4 genome

AF:

0.209

AC:

31798

AN:

151820

Hom.:

3686

Cov.:

AF XY:

0.207

AC XY:

15368

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.136

Gnomad4 AMR

AF:

0.222

Gnomad4 ASJ

AF:

0.275

Gnomad4 EAS

AF:

0.0541

Gnomad4 SAS

AF:

0.257

Gnomad4 FIN

AF:

0.186

Gnomad4 NFE

AF:

0.256

Gnomad4 OTH

AF:

0.242

Alfa

AF:

0.241

Hom.:

2300

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

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

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

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. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

DANN

Benign

0.85

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over