ACTN2

actinin alpha 2, the group of Actinins

Basic information

Region (hg38): 1:236664141-236764631

Links

ENSG00000077522 ∙ NCBI:88 ∙ OMIM:102573 ∙ HGNC:164 ∙ Uniprot:P35609 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• dilated cardiomyopathy 1AA (Moderate), mode of inheritance: AD
• heart conduction disease (Limited), mode of inheritance: AD
• dilated cardiomyopathy 1AA (Moderate), mode of inheritance: AD
• myopathy, congenital, with structured cores and z-line abnormalities (Moderate), mode of inheritance: AD
• intrinsic cardiomyopathy (Moderate), mode of inheritance: AD
• familial isolated dilated cardiomyopathy (Supportive), mode of inheritance: AD
• dilated cardiomyopathy 1AA (Limited), mode of inheritance: AD
• myopathy, distal, 6, adult-onset, autosomal dominant (Limited), mode of inheritance: Unknown
• myopathy, congenital, with structured cores and z-line abnormalities (Strong), mode of inheritance: AD
• intrinsic cardiomyopathy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cardiomyopathy, dilated, 1AA, with or without left ventricular noncompaction; Cardiomyopathy, hypertrophic 23, with or without left ventricular noncompaction; Congenital myopathy 8	AD	Cardiovascular	Preventive measures and medical management of cardiomyopathy may be helpful to help decrease morbidity and mortality	Cardiovascular; Musculoskeletal	14567970; 20301486; 20022194; 20301725; 25173926; 25224718; 30701273; 30900782

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ACTN2 gene.

• not provided (2 variants)
• Dilated cardiomyopathy 1AA (2 variants)
• Cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction (1 variants)
• not specified (1 variants)
• Primary dilated cardiomyopathy;Hypertrophic cardiomyopathy (1 variants)
• Primary familial hypertrophic cardiomyopathy;Dilated cardiomyopathy 1AA (1 variants)
• ACTN2-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ACTN2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	257	7	268
missense	1	5	485	35	9	535
nonsense	1	2	24			27
start loss			2			2
frameshift		3	13			16
inframe indel		1	6			7
splice donor/acceptor (+/-2bp)	2	2	18	1		23
splice region			43	45	4	92
non coding			44	173	84	301
Total	4	13	596	466	100

Variants in ACTN2

This is a list of pathogenic ClinVar variants found in the ACTN2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-236686164-C-T			Benign (Jun 19, 2018)
1-236686451-C-T		Dilated cardiomyopathy 1AA	Uncertain significance (Jan 13, 2018)
1-236686477-C-A			Likely benign (Jul 07, 2018)
1-236686515-C-T		Dilated cardiomyopathy 1AA	Uncertain significance (Jan 13, 2018)
1-236686570-C-A		Dilated cardiomyopathy 1AA	Uncertain significance (Jan 12, 2018)
1-236686571-GCGCCCGC-G		Dilated Cardiomyopathy, Dominant • Hypertrophic cardiomyopathy	Likely benign (Jun 14, 2016)
1-236686571-G-GCGCCCGC		Hypertrophic cardiomyopathy • Dilated Cardiomyopathy, Dominant	Conflicting classifications of pathogenicity (Sep 29, 2019)
1-236686631-C-G		not specified	Likely benign (Jun 12, 2017)
1-236686652-C-T		not specified • Hypertrophic cardiomyopathy • Dilated cardiomyopathy 1AA	Benign/Likely benign (Jun 14, 2016)
1-236686656-C-A		not specified	Conflicting classifications of pathogenicity (Jun 17, 2024)
1-236686667-G-A		Dilated cardiomyopathy 1AA	Uncertain significance (Jan 12, 2018)
1-236686671-G-T		Hypertrophic cardiomyopathy • Cardiomyopathy • Cardiovascular phenotype • not specified	Conflicting classifications of pathogenicity (Oct 03, 2024)
1-236686672-CCATGAA-C		Dilated cardiomyopathy 1AA;Primary familial hypertrophic cardiomyopathy	Uncertain significance (Dec 11, 2019)
1-236686674-A-G		Dilated cardiomyopathy 1AA;Primary familial hypertrophic cardiomyopathy	Uncertain significance (May 11, 2023)
1-236686679-C-A		Dilated cardiomyopathy 1AA;Primary familial hypertrophic cardiomyopathy	Uncertain significance (Dec 11, 2023)
1-236686679-C-G		Primary familial hypertrophic cardiomyopathy;Dilated cardiomyopathy 1AA	Uncertain significance (Dec 02, 2022)
1-236686681-A-G		Dilated cardiomyopathy 1AA;Primary familial hypertrophic cardiomyopathy	Uncertain significance (Mar 05, 2020)
1-236686682-G-T		Dilated cardiomyopathy 1AA;Primary familial hypertrophic cardiomyopathy	Uncertain significance (Mar 09, 2022)
1-236686685-A-G		Primary familial hypertrophic cardiomyopathy;Dilated cardiomyopathy 1AA	Uncertain significance (Nov 17, 2021)
1-236686689-C-G		Primary familial hypertrophic cardiomyopathy;Dilated cardiomyopathy 1AA	Uncertain significance (Dec 21, 2023)
1-236686689-C-T		Primary familial hypertrophic cardiomyopathy;Dilated cardiomyopathy 1AA	Uncertain significance (Sep 01, 2023)
1-236686690-C-G		Dilated cardiomyopathy 1AA;Primary familial hypertrophic cardiomyopathy	Uncertain significance (Apr 27, 2021)
1-236686691-C-A		not specified • Hypertrophic cardiomyopathy • Cardiovascular phenotype • Primary familial hypertrophic cardiomyopathy;Dilated cardiomyopathy 1AA • ACTN2-related disorder	Conflicting classifications of pathogenicity (Jan 26, 2024)
1-236686691-C-T		not specified • Primary familial hypertrophic cardiomyopathy;Dilated cardiomyopathy 1AA • Cardiovascular phenotype	Benign/Likely benign (Nov 27, 2023)
1-236686692-G-A		Dilated cardiomyopathy 1AA;Primary familial hypertrophic cardiomyopathy • Cardiomyopathy • Cardiovascular phenotype	Uncertain significance (Aug 02, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ACTN2	protein_coding	protein_coding	ENST00000366578	21	78178

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000317	125735	0	13	125748	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.29	446	530	0.842	0.0000355	5968
Missense in Polyphen		197	266.88	0.73815		3096
Synonymous	0.326	205	211	0.971	0.0000154	1631
Loss of Function	5.73	6	49.6	0.121	0.00000235	570

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000904	0.0000904
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000715	0.0000703
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000653	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein.
• Disease: DISEASE: Cardiomyopathy, familial hypertrophic 23, with or without left ventricular non-compaction (CMH23) [MIM:612158]: A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. {ECO:0000269|PubMed:20022194, ECO:0000269|PubMed:25173926}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cardiomyopathy, dilated 1AA, with or without left ventricular non-compaction (CMD1AA) [MIM:612158]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:14567970, ECO:0000269|PubMed:25224718}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);Arrhythmogenic Right Ventricular Cardiomyopathy;Striated Muscle Contraction;NO-cGMP-PKG mediated Neuroprotection;Signal Transduction;erk and pi-3 kinase are necessary for collagen binding in corneal epithelia;ucalpain and friends in cell spread;integrin signaling pathway;Neuronal System;Striated Muscle Contraction;Muscle contraction;Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;Hemostasis;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;Ras activation upon Ca2+ influx through NMDA receptor;CREB phosphorylation through the activation of Ras;Unblocking of NMDA receptor, glutamate binding and activation;CREB phosphorylation through the activation of CaMKII;Post NMDA receptor activation events;Activation of NMDA receptor and postsynaptic events;Nephrin family interactions;Cell-Cell communication;Signaling events mediated by focal adhesion kinase (Consensus)

Recessive Scores

• pRec: 0.399

Intolerance Scores

• loftool: 0.0829
• rvis_EVS: -1.72
• rvis_percentile_EVS: 2.47

Haploinsufficiency Scores

• pHI: 0.773
• hipred: Y
• hipred_score: 0.853
• ghis: 0.600

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.927

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Actn2

Zebrafish Information Network

• Gene name: actn2b
• Affected structure: cardiac muscle cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: MAPK cascade;platelet degranulation;cell adhesion;microspike assembly;muscle filament sliding;regulation of membrane potential;regulation of apoptotic process;negative regulation of potassium ion transport;positive regulation of potassium ion transport;sarcomere organization;focal adhesion assembly;protein homotetramerization;actin filament uncapping;cardiac muscle cell development;protein localization to plasma membrane;phospholipase C-activating angiotensin-activated signaling pathway;negative regulation of potassium ion transmembrane transporter activity;positive regulation of potassium ion transmembrane transporter activity;positive regulation of nucleic acid-templated transcription;negative regulation of protein localization to cell surface;positive regulation of endocytic recycling;positive regulation of cation channel activity
• Cellular component: extracellular region;cytosol;cytoskeleton;actin filament;plasma membrane;focal adhesion;Z disc;filopodium;cortical actin cytoskeleton;platelet alpha granule lumen;pseudopodium;dendritic spine;extracellular exosome;postsynaptic density membrane;glutamatergic synapse;postsynaptic density, intracellular component
• Molecular function: Ras guanyl-nucleotide exchange factor activity;integrin binding;calcium ion binding;protein binding;phosphatidylinositol-4,5-bisphosphate binding;cytoskeletal protein binding;structural constituent of muscle;protein domain specific binding;LIM domain binding;thyroid hormone receptor coactivator activity;titin binding;identical protein binding;protein homodimerization activity;ion channel binding;protein dimerization activity;actin filament binding;FATZ binding;titin Z domain binding