ACTA2

actin alpha 2, smooth muscle, the group of Actins

Basic information

Region (hg38): 10:88935073-88991339

Links

ENSG00000107796 ∙ NCBI:59 ∙ OMIM:102620 ∙ HGNC:130 ∙ Uniprot:P62736 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• aortic aneurysm, familial thoracic 6 (Strong), mode of inheritance: AD
• Moyamoya disease 5 (Strong), mode of inheritance: AD
• connective tissue disorder (Moderate), mode of inheritance: AD
• familial thoracic aortic aneurysm and aortic dissection (Supportive), mode of inheritance: AD
• multisystemic smooth muscle dysfunction syndrome (Supportive), mode of inheritance: Unknown
• multisystemic smooth muscle dysfunction syndrome (Definitive), mode of inheritance: AD
• Moyamoya disease 5 (Strong), mode of inheritance: AD
• multisystemic smooth muscle dysfunction syndrome (Strong), mode of inheritance: AD
• aortic aneurysm, familial thoracic 6 (Strong), mode of inheritance: AD
• familial thoracic aortic aneurysm and aortic dissection (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Moyamoya disease 5; Multisystemic smooth muscle dysfunction syndrome; Aortic aneurysm, familial thoracic 6	AD	Cardiovascular	Surveillance for cardiovascular complications (eg, aortic aneurysm), as well as related preventive measures to help control contributory factors may reduce morbidity and mortality by allowing early diagnosis and treatment; There has been a reported increased risk of aortic dissection with minimal aortic dilatation during the pregnancies of affected women, and awareness may allow monitoring and management	Cardiovascular; Dermatologic; Musculoskeletal; Neurologic; Ophthalmologic	17994018; 19409525; 22051261; 22302747; 24243736; 29300374

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ACTA2 gene.

• Aortic aneurysm, familial thoracic 6 (278 variants)
• Familial thoracic aortic aneurysm and aortic dissection (208 variants)
• not provided (138 variants)
• not specified (33 variants)
• Multisystemic smooth muscle dysfunction syndrome (22 variants)
• Aortic aneurysm, familial thoracic 6;Multisystemic smooth muscle dysfunction syndrome;Moyamoya disease 5 (8 variants)
• Connective tissue disorder (5 variants)
• Moyamoya disease 5 (5 variants)
• Moyamoya disease (4 variants)
• Inborn genetic diseases (3 variants)
• Familial aortopathy (3 variants)
• Isolated thoracic aortic aneurysm (3 variants)
• Cardiovascular phenotype (2 variants)
• Multisystemic smooth muscle dysfunction syndrome;Moyamoya disease 5;Aortic aneurysm, familial thoracic 6 (2 variants)
• Thoracic aortic aneurysm (1 variants)
• alterations of great arteries and veins;Connective tissue disorder (1 variants)
• See cases (1 variants)
• Aneurysm of descending aorta;Arterial tortuosity (1 variants)
• Aortic aneurysm, familial thoracic 2 (1 variants)
• ACTA2-Related Disorders (1 variants)
• Descending aortic dissection (1 variants)
• ACTA2-related condition (1 variants)
• Multisystemic smooth muscle dysfunction syndrome;Aortic aneurysm, familial thoracic 6 (1 variants)
• Connective tissue dysplasia (1 variants)
• Aortic aneurysm, familial thoracic 6;Multisystemic smooth muscle dysfunction syndrome;Moyamoya disease 5;Congenital aneurysm of ascending aorta;Moyamoya disease (1 variants)
• Aortic aneurysm, familial thoracic 6;Moyamoya disease 5;Multisystemic smooth muscle dysfunction syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ACTA2 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			3	95		98
missense	5	16	180			201
nonsense		1	8			9
start loss			2			2
frameshift		1	13			14
inframe indel			3			3
splice donor/acceptor (+/-2bp)	2	2	4			8
splice region			14	13		27
non coding			10	43	16	69
Total	7	20	223	138	16

Highest pathogenic variant AF is 0.00000657

Variants in ACTA2

This is a list of pathogenic ClinVar variants found in the ACTA2 region.

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

Position	Type	Phenotype	Significance	ClinVar
10-88935101-A-G		Multisystemic smooth muscle dysfunction syndrome • Moyamoya disease • Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Jun 14, 2016)
10-88935118-C-A		Aortic aneurysm, familial thoracic 6 • Multisystemic smooth muscle dysfunction syndrome	Conflicting classifications of pathogenicity (Jan 12, 2018)
10-88935119-G-C		Multisystemic smooth muscle dysfunction syndrome • Aortic aneurysm, familial thoracic 6	Uncertain significance (Jan 13, 2018)
10-88935180-T-C		Multisystemic smooth muscle dysfunction syndrome • Aortic aneurysm, familial thoracic 6	Uncertain significance (Jan 13, 2018)
10-88935184-CAGTTGTGTGCTAGAGACAGAGAGGAGCAGGAAA-C		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Jun 26, 2023)
10-88935195-T-A		Multisystemic smooth muscle dysfunction syndrome • Moyamoya disease • Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Jun 14, 2016)
10-88935218-G-A		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Jul 13, 2020)
10-88935220-G-A		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Aug 15, 2023)
10-88935224-T-C		Familial thoracic aortic aneurysm and aortic dissection	Likely benign (Apr 01, 2019)
10-88935225-A-G		Aortic aneurysm, familial thoracic 6 • Familial thoracic aortic aneurysm and aortic dissection • ACTA2-related disorder	Uncertain significance (May 18, 2023)
10-88935226-G-A		Familial thoracic aortic aneurysm and aortic dissection	Likely benign (Nov 20, 2023)
10-88935230-CA-C		Aortic aneurysm, familial thoracic 6	Uncertain significance (Sep 02, 2021)
10-88935236-C-T		Familial thoracic aortic aneurysm and aortic dissection • Aortic aneurysm, familial thoracic 6	Uncertain significance (Feb 05, 2024)
10-88935237-G-A		Familial thoracic aortic aneurysm and aortic dissection • Aortic aneurysm, familial thoracic 6	Uncertain significance (Dec 01, 2023)
10-88935242-A-G		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Jul 10, 2023)
10-88935245-A-G		Aortic aneurysm, familial thoracic 6	Uncertain significance (Oct 03, 2021)
10-88935245-A-T		Aortic aneurysm, familial thoracic 6	Uncertain significance (Dec 22, 2023)
10-88935248-G-C		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Jan 11, 2024)
10-88935248-G-T		Aortic aneurysm, familial thoracic 6	Uncertain significance (Jun 13, 2023)
10-88935255-C-A		Aortic aneurysm, familial thoracic 6	Uncertain significance (Sep 30, 2023)
10-88935255-C-T		Aortic aneurysm, familial thoracic 6	Uncertain significance (Apr 06, 2019)
10-88935256-G-A		Familial thoracic aortic aneurysm and aortic dissection	Likely benign (Mar 28, 2023)
10-88935257-G-A		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Jan 27, 2020)
10-88935262-A-C		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Oct 23, 2023)
10-88935264-C-T		Familial thoracic aortic aneurysm and aortic dissection	Uncertain significance (Sep 17, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ACTA2	protein_coding	protein_coding	ENST00000458208	8	56317

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.930	0.0698	125671	0	6	125677	0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.20	91	227	0.402	0.0000141	2490
Missense in Polyphen		18	82.097	0.21925		898
Synonymous	1.08	72	84.7	0.850	0.00000541	737
Loss of Function	3.41	2	17.3	0.116	9.34e-7	201

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000353	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
• Disease: DISEASE: Note=ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, premature onset coronary artery disease (CAD), premature ischemic strokes and Moyamoya disease. {ECO:0000269|PubMed:19409525}.; DISEASE: Aortic aneurysm, familial thoracic 6 (AAT6) [MIM:611788]: A disease characterized by permanent dilation of the thoracic aorta usually due to degenerative changes in the aortic wall. It is primarily associated with a characteristic histologic appearance known as 'medial necrosis' or 'Erdheim cystic medial necrosis' in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance. {ECO:0000269|PubMed:17994018, ECO:0000269|PubMed:19409525, ECO:0000269|PubMed:19639654}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Moyamoya disease 5 (MYMY5) [MIM:614042]: A progressive cerebral angiopathy characterized by bilateral intracranial carotid artery stenosis and telangiectatic vessels in the region of the basal ganglia. The abnormal vessels resemble a 'puff of smoke' (moyamoya) on cerebral angiogram. Affected individuals can develop transient ischemic attacks and/or cerebral infarction, and rupture of the collateral vessels can cause intracranial hemorrhage. Hemiplegia of sudden onset and epileptic seizures constitute the prevailing presentation in childhood, while subarachnoid bleeding occurs more frequently in adults. {ECO:0000269|PubMed:20970362}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multisystemic smooth muscle dysfunction syndrome (MSMDYS) [MIM:613834]: A syndrome characterized by dysfunction of smooth muscle cells throughout the body, leading to aortic and cerebrovascular disease, fixed dilated pupils, hypotonic bladder, malrotation, and hypoperistalsis of the gut and pulmonary hypertension. {ECO:0000269|PubMed:20734336}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Relaxin signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);Myometrial Relaxation and Contraction Pathways;Striated Muscle Contraction;Protein alkylation leading to liver fibrosis;Smooth Muscle Contraction;Muscle contraction;EGFR1;PDGFR-beta signaling pathway (Consensus)

Recessive Scores

• pRec: 0.156

Intolerance Scores

• loftool: 0.129
• rvis_EVS: -0.27
• rvis_percentile_EVS: 33.97

Haploinsufficiency Scores

• pHI: 0.767
• hipred: Y
• hipred_score: 0.698
• ghis: 0.651

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.834

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Acta2
• Phenotype: muscle phenotype; vision/eye phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: acta2
• Affected structure: intestine
• Phenotype tag: abnormal
• Phenotype quality: non-contractile

Gene ontology

• Biological process: muscle contraction;regulation of blood pressure;response to virus;positive regulation of gene expression;vascular smooth muscle contraction;positive regulation of transcription, DNA-templated;glomerular mesangial cell development;mesenchyme migration
• Cellular component: extracellular space;cytoplasm;cytosol;actin cytoskeleton;lamellipodium;filopodium;smooth muscle contractile fiber;protein-containing complex;cell body;extracellular exosome
• Molecular function: ATP binding;protein kinase binding