Genetic Variant ACTN3:p.Cys12Arg (chr11-66546544-T-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001258371.3(ACTN3):c.34T>C(p.Cys12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,535,326 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 8 hom. )

Consequence

ACTN3
NM_001258371.3 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.21

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008911639).

BP6

Variant 11-66546544-T-C is Benign according to our data. Variant chr11-66546544-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3057224.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001258371.3 link	c.34T>C	p.Cys12Arg	missense_variant	Exon 1 of 21		NP_001245300.2	Q08043A0A087WSZ2B4DZQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN3	ENST00000502692.5 link	c.34T>C	p.Cys12Arg	missense_variant	Exon 1 of 21	2		ENSP00000422007.1		A0A087WSZ2

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

235

AN:

151888

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00142

AC:

182

AN:

128284

AF XY:

0.00149

show subpopulations

Gnomad AFR exome

AF:

0.000657

Gnomad AMR exome

AF:

0.000698

Gnomad ASJ exome

AF:

0.000742

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00149

Gnomad NFE exome

AF:

0.00254

Gnomad OTH exome

AF:

0.00100

GnomAD4 exome

AF:

0.00186

AC:

2572

AN:

1383320

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

1256

AN XY:

682570

show subpopulations

African (AFR)

AF:

0.000285

AC:

AN:

31588

American (AMR)

AF:

0.000644

AC:

AN:

35690

Ashkenazi Jewish (ASJ)

AF:

0.000675

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.00107

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00111

AC:

AN:

33470

Middle Eastern (MID)

AF:

0.000879

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00215

AC:

2315

AN:

1078844

Other (OTH)

AF:

0.00140

AC:

AN:

57892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

142

284

425

567

709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00155

AC:

235

AN:

152006

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41466

American (AMR)

AF:

0.000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00125

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00281

AC:

191

AN:

67956

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00265

Hom.:

Bravo

AF:

0.00133

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00156

AC:

ExAC

AF:

0.00108

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ACTN3-related disorder

Benign:1

Sep 13, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

2.0

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.22

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0089

PhyloP100

-1.2

PrimateAI

Benign

0.41

Vest4

0.048

MVP

0.70

GERP RS

-3.0

PromoterAI

0.062

Neutral

(source)

gMVP

0.28

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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11-66546544-T-C

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