• 1
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
ACTA2 (HGNC:130) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
actin alpha 2, smooth muscle
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
ACTSA
%HI
2.61(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.93(Read more about gnomAD pLI score)
LOEUF
0.36(Read more about gnomAD LOEUF score)
Cytoband
10q23.31
Genomic Coordinates
GRCh37/hg19: chr10:90694831-90751154 NCBI Ensembl UCSC
GRCh38/hg38: chr10:88935074-88991337 NCBI Ensembl UCSC
MANE Select Transcript
NM_001613.4 ENST00000224784.10 (Read more about MANE Select)
Function
Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-18333
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Little Evidence for Haploinsufficiency (1)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
09/28/2022

Haploinsufficiency (HI) Score Details

HI Score:
1
HI Evidence Strength:
Little Evidence for Haploinsufficiency (Disclaimer)
HI Evidence:
  • PUBMED: 32209317
    Zhao et al., 2020 performed WES in 73 Chinese patients with sporadic non-syndromic type A thoracic aneurysm and dissections. A nonsense variant, c.216delG, p.Ile73* in ACTA2 was identified in one 47 year old man with a Z-score of 7.93 and aortic insufficiency. No family studies or functional studies were performed.
  • PUBMED: 30056620
    Zheng et al., 2018 performed NGS of 69 genes associated with aortic dissections and aneurysms in 59 individuals with sporadic acute aortic dissections. A frameshifting variant, c.319delC/p.L107Sfs*6 in ACTA2 was identified in one 37 year old man with a type A aortic dissection. No family studies or functional studies were performed.
  • PUBMED: 34498425
    Li et al., 2021 performed NGS of 15 genes associated with thoracic aortic aneurysm and dissection (TAAD) in 212 individuals with various aortic phenotypes. Two variants, including a 1bp deletion resulting in a nonsense variant, c.583delC, p.Leu195* in ACTA2, and an intronic variant (reported as IVS2-9C>G) in MYLK, were identified in a 46 year old proband with a diagnosis of TAAD who had a strong family history of sudden death and aortic dissection. 3 siblings for whom testing was not able to be performed were reported to have died suddenly around the age of 35. One living brother with an aortic dissection at 39 was tested and found to carry both variants. Both parents were reported to be living without a TAAD diagnosis; both the ACTA2 and the MYLK variants were found to be inherited from the 73 year old mother.
HI Evidence Comments:
Variants in ACTA2 have been observed in individuals with several related phenotypes: thoracic aortic aneurysms and dissections (TAAD); Moyamoya disease; and multisystemic smooth muscle dysfunction syndrome (see OMIM 102620 for additional information). To date, the majority of reported pathogenic variants are missense variants. Published functional studies, including Guo, et al., 2007, Malloy, et al., 2012, and Burger, et al., 2021, suggest that the tested missense variants appear to interfere with actin filament structure and stabilization and exert a dominant negative effect on the protein (PMID:17994018, PMID:34244757, PMID:22753406). Several variants have been reported that would be predicted to result in premature truncation of the protein. Renard et al., 2013, describes two multi-generational families with aortic aneurysms, each segregating for one of two truncating variants, c.940C>T/p.Arg314* and c.1019_1020delCT/p.Ser340Cysfs*25. However, both variants occur in the final two exons of the gene and are predicted to escape nonsense mediated decay; the authors suggested that these variants could still exert a dominant negative effect, though functional studies were not performed (PMID:21937134). Other families have been reported to carry predicted loss of function variants in ACTA2, however these families have been complicated by the presence of other variants in other genes related to aortic aneurysm risk. Keravnou et al., 2018, reported a two generation family in which a frameshifting variant in ACTA2, c.363_367delGAGTC, p.Met121Ilefs*5, was identified in a pair of affected siblings as well as their mother. However, the siblings were also found to carry a missense variant in MYH11 (c.3234C>G, p.Ile1078Met). This MYH11 variant was found to be inherited from their father, who had an aortic aneurysm requiring surgery (PMID: 30526509). In addition, Li et al., 2021, reported a family with a predicted nonsense variant c.583delC/p.Leu195* in ACTA2, identified in two brothers with thoracic aortic aneurysm and dissection (TAAD) diagnoses. However both brothers were also found to carry an intronic splice region variant in MYLK. Both the ACTA2 and MYLK variants were inherited from the mother who was reported to be living at the age of 73 (PMID: 34498425). Additionally, there are additional reports of affected individuals carrying predicted loss of function variants in ACTA2, however no family studies or functional studies have been performed. Zhao et al., 2020, performed whole exome sequencing in 73 patients with sporadic non-syndromic type A thoracic aneurysm and dissection and identified a frameshift variant (c.216delG/p.Ile73*) in one 47 year old man (PMID:32209317). In addition, Zheng et al., 2018, sequenced 69 genes in a cohort of 59 patients with acute aortic dissection and identified a frameshift variant (c.319delC/p.L107Sfs*6) in a 37 year old man with a type A aneurysm (PMID:30056620). Last, Li et al., 2021, reported a frameshift variant (c.814delG, p.Glu272fs) in one individual in a cohort of 212 participants with various aortic phenotypes (PMID: 34498425). At this time, while predicted loss of function variants have been reported in a small number of individuals affected by ACTA2-related conditions, none of these reports have provided clear evidence that these variants are disease-causing. Additionally, there have been no functional studies that have shown conclusively that loss of function variants in ACTA2 are relevant to disease.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
No evidence of triplosensitivity.

Genomic View

Select assembly: (NC_000010.10) (NC_000010.11)