11-66562261-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001104.4(ACTN3):c.2327A>G(p.Gln776Arg) variant causes a missense change. The variant allele was found at a frequency of 0.555 in 1,613,402 control chromosomes in the GnomAD database, including 253,659 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.61 ( 29593 hom., cov: 30)

Exomes 𝑓: 0.55 ( 224066 hom. )

Consequence

ACTN3
NM_001104.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.67

Publications

53 publications found

Variant links:

Genes affected

ACTN3 (HGNC:165): (actinin alpha 3) This gene encodes a member of the alpha-actin binding protein gene family. The encoded protein is primarily expressed in skeletal muscle and functions as a structural component of sarcomeric Z line. This protein is involved in crosslinking actin containing thin filaments. An allelic polymorphism in this gene results in both coding and non-coding variants; the reference genome represents the coding allele. The non-functional allele of this gene is associated with elite athlete status. [provided by RefSeq, Feb 2014]

ACTN3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.3758257E-7).

BP6

Variant 11-66562261-A-G is Benign according to our data. Variant chr11-66562261-A-G is described in CliVar as Benign. Clinvar id is 3060488.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-66562261-A-G is described in CliVar as Benign. Clinvar id is 3060488.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-66562261-A-G is described in CliVar as Benign. Clinvar id is 3060488.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-66562261-A-G is described in CliVar as Benign. Clinvar id is 3060488.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-66562261-A-G is described in CliVar as Benign. Clinvar id is 3060488.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-66562261-A-G is described in CliVar as Benign. Clinvar id is 3060488.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4 link	c.2327A>G	p.Gln776Arg	missense_variant	Exon 19 of 21	ENST00000513398.2	NP_001095.2	Q08043B4DZQ2
ACTN3	NM_001258371.3 link	c.2456A>G	p.Gln819Arg	missense_variant	Exon 19 of 21		NP_001245300.2	Q08043A0A087WSZ2B4DZQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN3	ENST00000513398.2 link	c.2327A>G	p.Gln776Arg	missense_variant	Exon 19 of 21	1	NM_001104.4	ENSP00000426797.1		Q08043
ACTN3	ENST00000502692.5 link	c.2456A>G	p.Gln819Arg	missense_variant	Exon 19 of 21	2		ENSP00000422007.1		A0A087WSZ2

Frequencies

GnomAD3 genomes

AF:

0.611

AC:

92763

AN:

151730

Hom.:

29542

Cov.:

show subpopulations

Gnomad AFR

AF:

0.792

Gnomad AMI

AF:

0.434

Gnomad AMR

AF:

0.445

Gnomad ASJ

AF:

0.549

Gnomad EAS

AF:

0.534

Gnomad SAS

AF:

0.417

Gnomad FIN

AF:

0.688

Gnomad MID

AF:

0.579

Gnomad NFE

AF:

0.553

Gnomad OTH

AF:

0.582

GnomAD2 exomes

AF:

0.533

AC:

132907

AN:

249310

AF XY:

0.533

show subpopulations

Gnomad AFR exome

AF:

0.790

Gnomad AMR exome

AF:

0.330

Gnomad ASJ exome

AF:

0.562

Gnomad EAS exome

AF:

0.552

Gnomad FIN exome

AF:

0.679

Gnomad NFE exome

AF:

0.558

Gnomad OTH exome

AF:

0.529

GnomAD4 exome

AF:

0.549

AC:

802611

AN:

1461552

Hom.:

224066

Cov.:

AF XY:

0.547

AC XY:

397433

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.804

AC:

26912

AN:

33480

American (AMR)

AF:

0.344

AC:

15366

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.554

AC:

14482

AN:

26134

East Asian (EAS)

AF:

0.514

AC:

20395

AN:

39698

South Asian (SAS)

AF:

0.427

AC:

36843

AN:

86258

European-Finnish (FIN)

AF:

0.673

AC:

35898

AN:

53312

Middle Eastern (MID)

AF:

0.537

AC:

3090

AN:

5758

European-Non Finnish (NFE)

AF:

0.554

AC:

616323

AN:

1111824

Other (OTH)

AF:

0.552

AC:

33302

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

22456

44913

67369

89826

112282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17288

34576

51864

69152

86440

<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:

0.612

AC:

92863

AN:

151850

Hom.:

29593

Cov.:

AF XY:

0.611

AC XY:

45314

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.792

AC:

32785

AN:

41392

American (AMR)

AF:

0.445

AC:

6785

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.549

AC:

1902

AN:

3466

East Asian (EAS)

AF:

0.534

AC:

2747

AN:

5142

South Asian (SAS)

AF:

0.418

AC:

2009

AN:

4808

European-Finnish (FIN)

AF:

0.688

AC:

7276

AN:

10574

Middle Eastern (MID)

AF:

0.582

AC:

171

AN:

294

European-Non Finnish (NFE)

AF:

0.553

AC:

37578

AN:

67904

Other (OTH)

AF:

0.576

AC:

1214

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1736

3472

5207

6943

8679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

750

1500

2250

3000

3750

<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:

0.568

Hom.:

105877

Bravo

AF:

0.602

TwinsUK

AF:

0.555

AC:

2057

ALSPAC

AF:

0.554

AC:

2136

ESP6500AA

AF:

0.786

AC:

3316

ESP6500EA

AF:

0.550

AC:

4656

ExAC

AF:

0.542

AC:

65594

Asia WGS

AF:

0.498

AC:

1731

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ACTN3-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.21

T;T

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.33

T;T

MetaRNN

Benign

9.4e-7

T;T

PhyloP100

3.7

PrimateAI

Uncertain

0.63

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.022

GERP RS

5.7

Varity_R

0.048

gMVP

0.39

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