10-88947270-G-C
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_001613.4(ACTA2):c.246C>G(p.Asp82Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 31)
Consequence
ACTA2
NM_001613.4 missense
NM_001613.4 missense
Scores
7
2
9
Clinical Significance
Conservation
PhyloP100: -0.285
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTA2. . Trascript score misZ: 4.6117 (greater than threshold 3.09). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. GenCC has associacion of the gene with familial thoracic aortic aneurysm and aortic dissection, connective tissue disorder, aortic aneurysm, familial thoracic 6, multisystemic smooth muscle dysfunction syndrome, Moyamoya disease 5.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.934
PP5
Variant 10-88947270-G-C is Pathogenic according to our data. Variant chr10-88947270-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 536918.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Aortic aneurysm, familial thoracic 6 Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 11, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTA2 protein function. ClinVar contains an entry for this variant (Variation ID: 536918). This missense change has been observed in individuals with thoracic aortic aneurysms or dissections (PMID: 21212136; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 82 of the ACTA2 protein (p.Asp82Glu). - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Likely pathogenic and reported on 02-22-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 22, 2018 | The p.D82E variant (also known as c.246C>G), located in coding exon 2 of the ACTA2 gene, results from a C to G substitution at nucleotide position 246. The aspartic acid at codon 82 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been detected in a proband and parent with type A aortic dissections, and biopsy of aortic media showed reduced smooth muscle cell alpha-actin immunostaining (Disabella E et al. Heart, 2011 Feb;97:321-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 22, 2024 | PP1, PP2, PM2, PS4_moderate - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;D;D
REVEL
Pathogenic
Sift4G
Benign
T;.;.
Polyphen
B;.;.
Vest4
MutPred
Loss of ubiquitination at K86 (P = 0.1647);Loss of ubiquitination at K86 (P = 0.1647);Loss of ubiquitination at K86 (P = 0.1647);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at