rs2288601

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001103.4(ACTN2):c.877-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.774 in 1,613,424 control chromosomes in the GnomAD database, including 483,263 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 45892 hom., cov: 28)

Exomes 𝑓: 0.77 ( 437371 hom. )

Consequence

ACTN2
NM_001103.4 splice_region, intron

Scores

Splicing: ADA: 0.3121

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.14

Publications

18 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 1-236739294-C-G is Benign according to our data. Variant chr1-236739294-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ACTN2	NM_001103.4 link	c.877-8C>G	splice_region_variant, intron_variant	Intron 9 of 20	ENST00000366578.6	NP_001094.1
ACTN2	NM_001278343.2 link	c.877-8C>G	splice_region_variant, intron_variant	Intron 9 of 20		NP_001265272.1
ACTN2	NR_184402.1 link	n.1249-8C>G	splice_region_variant, intron_variant	Intron 11 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN2	ENST00000366578.6 link	c.877-8C>G		splice_region_variant, intron_variant	Intron 9 of 20	1	NM_001103.4	ENSP00000355537.4

Frequencies

GnomAD3 genomes

AF:

0.778

AC:

117965

AN:

151600

Hom.:

45849

Cov.:

show subpopulations

Gnomad AFR

AF:

0.780

Gnomad AMI

AF:

0.673

Gnomad AMR

AF:

0.770

Gnomad ASJ

AF:

0.766

Gnomad EAS

AF:

0.788

Gnomad SAS

AF:

0.760

Gnomad FIN

AF:

0.806

Gnomad MID

AF:

0.766

Gnomad NFE

AF:

0.777

Gnomad OTH

AF:

0.778

GnomAD2 exomes

AF:

0.775

AC:

194706

AN:

251200

AF XY:

0.776

show subpopulations

Gnomad AFR exome

AF:

0.777

Gnomad AMR exome

AF:

0.753

Gnomad ASJ exome

AF:

0.772

Gnomad EAS exome

AF:

0.800

Gnomad FIN exome

AF:

0.799

Gnomad NFE exome

AF:

0.776

Gnomad OTH exome

AF:

0.775

GnomAD4 exome

AF:

0.773

AC:

1130201

AN:

1461706

Hom.:

437371

Cov.:

AF XY:

0.774

AC XY:

562572

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.770

AC:

25771

AN:

33480

American (AMR)

AF:

0.758

AC:

33913

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

20108

AN:

26136

East Asian (EAS)

AF:

0.769

AC:

30545

AN:

39698

South Asian (SAS)

AF:

0.767

AC:

66120

AN:

86248

European-Finnish (FIN)

AF:

0.798

AC:

42629

AN:

53398

Middle Eastern (MID)

AF:

0.751

AC:

4329

AN:

5768

European-Non Finnish (NFE)

AF:

0.773

AC:

860009

AN:

1111866

Other (OTH)

AF:

0.775

AC:

46777

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

13877

27755

41632

55510

69387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20546

41092

61638

82184

102730

<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:

0.778

AC:

118063

AN:

151718

Hom.:

45892

Cov.:

AF XY:

0.778

AC XY:

57667

AN XY:

74112

show subpopulations

African (AFR)

AF:

0.780

AC:

32213

AN:

41312

American (AMR)

AF:

0.770

AC:

11755

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.766

AC:

2658

AN:

3470

East Asian (EAS)

AF:

0.788

AC:

4055

AN:

5144

South Asian (SAS)

AF:

0.760

AC:

3632

AN:

4776

European-Finnish (FIN)

AF:

0.806

AC:

8486

AN:

10526

Middle Eastern (MID)

AF:

0.765

AC:

225

AN:

294

European-Non Finnish (NFE)

AF:

0.777

AC:

52789

AN:

67918

Other (OTH)

AF:

0.777

AC:

1638

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1311

2621

3932

5242

6553

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

864

1728

2592

3456

4320

<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:

0.766

Hom.:

11335

Bravo

AF:

0.775

Asia WGS

AF:

0.758

AC:

2638

AN:

3478

EpiCase

AF:

0.776

EpiControl

AF:

0.781

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 20, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 31, 2013

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

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:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Myopathy, congenital, with structured cores and z-line abnormalities

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

3.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.31

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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