rs139515659

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.1235C>T(p.Thr412Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,614,140 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T412T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

ACTN2
NM_001103.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: 1.32

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07533038).

BP6

Variant 1-236743023-C-T is Benign according to our data. Variant chr1-236743023-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43897.

BS2

High AC in GnomAd4 at 41 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ACTN2	NM_001103.4 link	c.1235C>T	p.Thr412Met	missense_variant	Exon 11 of 21	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2 link	c.1235C>T	p.Thr412Met	missense_variant	Exon 11 of 21		NP_001265272.1
ACTN2	NR_184402.1 link	n.1607C>T		non_coding_transcript_exon_variant	Exon 13 of 23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 link	c.1235C>T	p.Thr412Met	missense_variant	Exon 11 of 21	1	NM_001103.4	ENSP00000355537.4

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000954

AC:

AN:

251444

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000144

AC:

211

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000106

AC:

118

AN:

1112008

Other (OTH)

AF:

0.000182

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000269

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41544

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.000269

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 16, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 26, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29247119, 23861362, 24503780, 31994743) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACTN2: BS2 -

not specified

Uncertain:2

Feb 11, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Thr412Met variant in ACTN2 has now been identified by our laboratory in four individuals, two with DCM and two with HCM, one of whom carried a pathogenic va riant in another gene. In addition, this variant has been identified in 1/8600 E uropean American chromosomes and in 1/4406 African American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1395156 59) and in 1/1740 European chromosomes by the ClinSeq study (Ng 2013). Threonine (Thr) at position 412 is conserved in mammals, but not in evolutionarily distan t species and 2 fish species carry a methionine (Met) at this position, raising the possibility that this change may be tolerated. Computational prediction tool s also suggest this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Additional information is ne eded to fully assess the clinical significance of this variant. -

Jan 31, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Uncertain:1

Jun 08, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1AA

Uncertain:1

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA

Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 11, 2024

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

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

.;.;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.075

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.46

.;N;N

PhyloP100

1.3

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.24

.;N;N

REVEL

Benign

0.13

Sift

Benign

0.29

.;T;T

Sift4G

Uncertain

0.056

T;T;T

Polyphen

0.0090

.;.;B

Vest4

0.38

MVP

0.40

MPC

0.24

ClinPred

0.038

GERP RS

5.5

Varity_R

0.10

gMVP

0.17

Mutation Taster

=84/16

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