10-88938074-G-T

Variant names:

• chr10-88938074-G-T
• rs777832794
• NM_001613.4:c.977C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001613.4(ACTA2):​c.977C>A​(p.Thr326Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T326A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: ACTA2 NM_001613.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 10.0
• Publications: 4 publications found

Genes affected

ACTA2 (HGNC:130): (actin alpha 2, smooth muscle) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a smooth muscle actin that is involved in vascular contractility and blood pressure homeostasis. Mutations in this gene cause a variety of vascular diseases, such as thoracic aortic disease, coronary artery disease, stroke, and Moyamoya disease, as well as multisystemic smooth muscle dysfunction syndrome. [provided by RefSeq, Sep 2017]

STAMBPL1 (HGNC:24105): (STAM binding protein like 1) Predicted to enable Lys63-specific deubiquitinase activity and thiol-dependent deubiquitinase. Predicted to be involved in protein K63-linked deubiquitination. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACTA2-AS1 (HGNC:45169): (ACTA2 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP2: Missense variant in the ACTA2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Trascript score misZ: 4.6117 (above the threshold of 3.09). GenCC associations: The gene is linked to multisystemic smooth muscle dysfunction syndrome, connective tissue disorder, familial thoracic aortic aneurysm and aortic dissection, Moyamoya disease 5, aortic aneurysm, familial thoracic 6.
• BS2: High AC in GnomAdExome4 at 48 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTA2	NM_001613.4	c.977C>A	p.Thr326Asn	missense_variant	Exon 8 of 9	ENST00000224784.10	NP_001604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTA2	ENST00000224784.10	c.977C>A	p.Thr326Asn	missense_variant	Exon 8 of 9	1	NM_001613.4	ENSP00000224784.6

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152138 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000598 AC: 15 AN: 250886 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461686 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727170

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1111888

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152138 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has been reported in one individual with coronary artery stenosis and unrelated individuals with bicuspid aortic valve and thoracic aortic aneurysm (PMID: 19409525, 28659821); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20689142, 28848449, 28659821, 36053285, 19409525, 37937776) -

Sep 05, 2018

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 15, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACTA2 c.977C>A; p.Thr326Asn variant (rs777832794) is reported in the literature in individuals affected with bicuspid aortic valve, thoracic aortic aneurysm, and stroke (Gillis 2017, Guo 2009, Regalado 2015, van den Bersselaar 2022). This variant is also reported in ClinVar (Variation ID: 263430), and is found in the non-Finnish European population with an allele frequency of 0.013% (15/113270 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.504). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Gillis E et al. Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor. Front Physiol. 2017 Jun 13;8:400. PMID: 28659821. Guo DC et al. Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet. 2009 May;84(5):617-27. PMID: 19409525. Regalado ES et al. Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations. Circ Cardiovasc Genet. 2015 Jun;8(3):457-64. PMID: 25759435. van den Bersselaar LM et al. Expanding the genetic and phenotypic spectrum of ACTA2-related vasculopathies in a Dutch cohort. Genet Med. 2022 Oct;24(10):2112-2122. PMID: 36053285. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:3

Dec 21, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with asparagine at codon 326 of the ACTA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with thoracic aortic aneurysm and aortic dissection or ACTA2-related conditions (PMID: 19409525, 28659821, 36053285, ClinVar SCV000646322.2). This variant has also been observed in four individuals who had no history of aortic dissection or surgical repair of aortic aneurysms (PMID: 25759435). This variant has been identified in 15/250886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with asparagine at codon 326 of the ACTA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with thoracic aortic aneurysm and aortic dissection or ACTA2-related conditions (PMID: 19409525, 28659821, 36053285, ClinVar SCV000646322.2). This variant has also been observed in four individuals who had no history of aortic dissection or surgical repair of aortic aneurysms (PMID: 25759435). This variant has been identified in 15/250886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Apr 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T326N variant (also known as c.977C>A), located in coding exon 7 of the ACTA2 gene, results from a C to A substitution at nucleotide position 977. The threonine at codon 326 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported in a proband with an ascending aortic aneurysm and bicuspid aortic valve (BAV) and son with stroke at age 25, a proband with myocardial infarct due coronary artery stenosis, and an additional proband with BAV (Guo DC et al, Am. J. Hum. Genet. 2009 May; 84(5):617-27; Gillis E et al. Front Physiol. 2017 Jun;8:400). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not specified Uncertain:1

Sep 30, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACTA2 c.977C>A (p.Thr326Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250886 control chromosomes. The observed variant frequency is approximately 3.4 fold the estimated maximal expected allele frequency for a pathogenic variant in ACTA2 causing Aortopathy phenotype (1.8e-05), strongly suggesting that the variant is benign. c.977C>A has been reported in the literature in individuals affected with TAA, stroke, and myocardial infarction (Guo_2009, Gillis_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

Aortic aneurysm, familial thoracic 6;C3151201:Multisystemic smooth muscle dysfunction syndrome;C3279690:Moyamoya disease 5 Uncertain:1

May 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ACTA2-related disorder Uncertain:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACTA2 c.977C>A variant is predicted to result in the amino acid substitution p.Thr326Asn. This variant has been reported in three individuals from two families with symptoms consistent with ACTA2-related aortic disease (Guo et al. 2009. PubMed ID: 19409525). However, this variant has also been observed in four members of an additional family (median age: 55 years; range 35 -75 years) who were all negative for aortic aneurysm/dissection events at the time of study (Regalado et al. 2015. PubMed ID: 25759435). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Aortic aneurysm, familial thoracic 6 Uncertain:1

Dec 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 326 of the ACTA2 protein (p.Thr326Asn). This variant is present in population databases (rs777832794, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of ACTA2-related conditions (PMID: 19409525, 28659821, 37937776; internal data). ClinVar contains an entry for this variant (Variation ID: 263430). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACTA2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	0.0035	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.0	L
PhyloP100		10
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.50
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.89
MVP		0.67
ClinPred		0.40	T
GERP RS		6.1
Varity_R		0.77
gMVP		0.76
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs777832794; hg19: chr10-90697831;