rs34827377

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_001103.4(ACTN2):c.1383C>T(p.Ile461Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,614,120 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 7 hom. )

Consequence

ACTN2
NM_001103.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: -1.05

Publications

5 publications found

Variant links:

Genes affected

ACTN2 (HGNC:164): (actinin alpha 2) 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 muscle-specific, alpha actinin isoform that is expressed in both skeletal and cardiac muscles. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ACTN2 Gene-Disease associations (from GenCC):

intrinsic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen
myopathy, congenital, with structured cores and z-line abnormalities
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy 1AA
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
heart conduction disease
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
myopathy, distal, 6, adult-onset, autosomal dominant
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)

ACTN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 1-236744753-C-T is Benign according to our data. Variant chr1-236744753-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43904.

BP7

Synonymous conserved (PhyloP=-1.05 with no splicing effect.

BS2

High AC in GnomAd4 at 168 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4 link	c.1383C>T	p.Ile461Ile	synonymous_variant	Exon 12 of 21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NM_001278343.2 link	c.1383C>T	p.Ile461Ile	synonymous_variant	Exon 12 of 21		NP_001265272.1	P35609-2
ACTN2	NR_184402.1 link	n.1755C>T		non_coding_transcript_exon_variant	Exon 14 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 link	c.1383C>T	p.Ile461Ile	synonymous_variant	Exon 12 of 21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

168

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00195

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00104

AC:

260

AN:

250706

AF XY:

0.000966

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00168

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00187

AC:

2731

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

1339

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.00157

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.000394

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00224

AC:

2492

AN:

1111980

Other (OTH)

AF:

0.00200

AC:

121

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

170

339

509

678

848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.00110

AC:

168

AN:

152322

Hom.:

Cov.:

AF XY:

0.000913

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41588

American (AMR)

AF:

0.00124

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00196

AC:

133

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00150

Hom.:

Bravo

AF:

0.00129

EpiCase

AF:

0.00207

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACTN2: BP4, BP7 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:4

Aug 06, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ile461Ile in exon 12 of ACTN2: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.1% (86/66382) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs34827377). -

Mar 13, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Nov 20, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1AA

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 27, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

6.3

(source)

DANN

Benign

0.86

PhyloP100

-1.1

Mutation Taster

=286/14

polymorphism

(source)

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