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GeneBe

11-66546753-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_001258371.3(ACTN3):c.243C>G(p.Pro81=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,535,636 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0088 ( 21 hom., cov: 32)
Exomes 𝑓: 0.00092 ( 20 hom. )

Consequence

ACTN3
NM_001258371.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.282
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 11-66546753-C-G is Benign according to our data. Variant chr11-66546753-C-G is described in ClinVar as [Benign]. Clinvar id is 3050805.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.282 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00876 (1334/152208) while in subpopulation AFR AF= 0.0299 (1242/41522). AF 95% confidence interval is 0.0285. There are 21 homozygotes in gnomad4. There are 596 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ACTN3NM_001258371.3 linkuse as main transcriptc.243C>G p.Pro81= synonymous_variant 1/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ACTN3ENST00000502692.5 linkuse as main transcriptc.243C>G p.Pro81= synonymous_variant 1/212

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00875
AC:
1331
AN:
152090
Hom.:
21
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0299
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00432
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00767
GnomAD3 exomes
AF:
0.00206
AC:
277
AN:
134650
Hom.:
5
AF XY:
0.00132
AC XY:
97
AN XY:
73404
show subpopulations
Gnomad AFR exome
AF:
0.0316
Gnomad AMR exome
AF:
0.00270
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000889
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000378
Gnomad OTH exome
AF:
0.000483
GnomAD4 exome
AF:
0.000921
AC:
1274
AN:
1383428
Hom.:
20
Cov.:
32
AF XY:
0.000769
AC XY:
525
AN XY:
682602
show subpopulations
Gnomad4 AFR exome
AF:
0.0317
Gnomad4 AMR exome
AF:
0.00244
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000757
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000491
Gnomad4 OTH exome
AF:
0.00207
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00876
AC:
1334
AN:
152208
Hom.:
21
Cov.:
32
AF XY:
0.00801
AC XY:
596
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.0299
Gnomad4 AMR
AF:
0.00432
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00759
Alfa
AF:
0.00569
Hom.:
3
Bravo
AF:
0.0111
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

ACTN3-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 26, 2019This 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
BayesDel_noAF
Benign
-0.78
Cadd
Benign
3.2
Dann
Benign
0.50

Splicing

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.

Other links and lift over

dbSNP: rs150880895; hg19: chr11-66314224; API