NM_001103.4:c.26A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001103.4(ACTN2):c.26A>G(p.Gln9Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00112 in 1,565,058 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q9P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00067 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

ACTN2
NM_001103.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:9

Conservation

PhyloP100: 4.69

Publications

20 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0700877).

BP6

Variant 1-236686699-A-G is Benign according to our data. Variant chr1-236686699-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 18313.

BS2

High AC in GnomAd4 at 102 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN2	NM_001103.4 link	c.26A>G	p.Gln9Arg	missense_variant	Exon 1 of 21	ENST00000366578.6	NP_001094.1	P35609-1
ACTN2	NM_001278343.2 link	c.26A>G	p.Gln9Arg	missense_variant	Exon 1 of 21		NP_001265272.1	P35609-2
ACTN2	NR_184402.1 link	n.201A>G		non_coding_transcript_exon_variant	Exon 1 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 link	c.26A>G	p.Gln9Arg	missense_variant	Exon 1 of 21	1	NM_001103.4	ENSP00000355537.4		P35609-1

Frequencies

GnomAD3 genomes

AF:

0.000673

AC:

102

AN:

151600

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000956

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00133

Gnomad OTH

AF:

0.000960

GnomAD2 exomes

AF:

0.000714

AC:

156

AN:

218568

AF XY:

0.000660

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000674

Gnomad ASJ exome

AF:

0.00187

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00113

Gnomad OTH exome

AF:

0.000396

GnomAD4 exome

AF:

0.00116

AC:

1645

AN:

1413350

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

806

AN XY:

703316

show subpopulations

African (AFR)

AF:

0.000172

AC:

AN:

29146

American (AMR)

AF:

0.000578

AC:

AN:

39822

Ashkenazi Jewish (ASJ)

AF:

0.00213

AC:

AN:

24376

East Asian (EAS)

AF:

0.00

AC:

AN:

34214

South Asian (SAS)

AF:

0.00

AC:

AN:

81968

European-Finnish (FIN)

AF:

0.0000757

AC:

AN:

52806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5500

European-Non Finnish (NFE)

AF:

0.00135

AC:

1469

AN:

1087756

Other (OTH)

AF:

0.00159

AC:

AN:

57762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

182

272

363

454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.000672

AC:

102

AN:

151708

Hom.:

Cov.:

AF XY:

0.000580

AC XY:

AN XY:

74172

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41430

American (AMR)

AF:

0.000197

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0000956

AC:

AN:

10462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00133

AC:

AN:

67858

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.00108

Hom.:

Bravo

AF:

0.000729

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000718

AC:

Asia WGS

AF:

0.000291

AC:

AN:

3452

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Jun 14, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Gln9Arg varia nt in ACTN2 has been reported in 2 infants and 2 adults with DCM (including 1 ca rrying a pathogenic variant in another gene), 1 adult with DCM, Afib, AVNRT, 3 a dults with HCM, segregating with disease in 1 affected family member, (and inclu ding 1 carrying a pathogenic variant in another gene), 2 teenagers with LV dilat ion, and 1 adult with LVH (Mohapatra 2003, Bos 2006 abstract, LMM data).This var iant has been identified in 0.1% (71/64536) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121434525 ). In vitro functional studies provide some evidence that the p.Gln9Arg variant may impact protein function (Mohapatra 2003). However, these types of assays may not accurately represent biological function. While animal models provide some evidence for a disease-causing role, this has yet to be confirmed in patients (S anchez 2005 abstract). In summary, while the clinical significance of the p.Gln 9Arg variant is uncertain, these data suggest that it is more likely to be benig n. -

May 23, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 24, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1AA

Pathogenic:1Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Sep 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dilated cardiomyopathy 1AA;C5203349:Myopathy, distal, 6, adult-onset, autosomal dominant;C5231445:Myopathy, congenital, with structured cores and z-line abnormalities

Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACTN2 NM_001103.3 exon 1 p.Gln9Arg (c.26A>G): This variant has been reported in the literature in two individuals with DCM, but did not segregate with disease in one affected family member (Mohapatra 2003 PMID:14567970, Cuenca 2016 PMID:26899768). This variant is also present in 0.1% (135/116270) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-236849999-A-G) and is present in ClinVar (Variation ID:18313). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. An in vitro functional study did suggest an impact to the protein through disruption of interaction with MLP protein (Mohapatra 2003 PMID:14567970). However, this study may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Intrinsic cardiomyopathy

Benign:1

Jul 07, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

May 26, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ACTN2-related disorder

Benign:1

Sep 14, 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). -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 11, 2023

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Primary dilated cardiomyopathy

Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Cardiovascular phenotype

Benign:1

Nov 01, 2019

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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

.;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.53

T;T

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.070

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.69

N;N

PhyloP100

4.7

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.46

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.19

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.0

.;B

Vest4

0.59

MVP

0.98

MPC

0.91

ClinPred

0.065

GERP RS

3.7

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.17

gMVP

0.67

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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