NM_001613.4:c.246C>G

Variant names:

• chr10-88947270-G-C
• rs1254836237
• NM_001613.4:c.246C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

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). Synonymous variant affecting the same amino acid position (i.e. D82D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACTA2 NM_001613.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 O:1
• Conservation: PhyloP100: -0.285
• Publications: 5 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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• 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 VariationId is 536918.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001613.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	NM_001613.4	MANE Select	c.246C>G	p.Asp82Glu	missense	Exon 3 of 9	NP_001604.1
	ACTA2	NM_001141945.3		c.246C>G	p.Asp82Glu	missense	Exon 3 of 9	NP_001135417.1
	ACTA2	NM_001320855.2		c.246C>G	p.Asp82Glu	missense	Exon 3 of 9	NP_001307784.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTA2	ENST00000224784.10	TSL:1 MANE Select	c.246C>G	p.Asp82Glu	missense	Exon 3 of 9	ENSP00000224784.6
	ACTA2	ENST00000713598.1		c.246C>G	p.Asp82Glu	missense	Exon 3 of 9	ENSP00000518894.1
	ACTA2	ENST00000415557.2	TSL:3	c.246C>G	p.Asp82Glu	missense	Exon 3 of 9	ENSP00000396730.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aortic aneurysm, familial thoracic 6 Pathogenic:1 Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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.

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with thoracic aortic aneurysms or dissections (PMID: 21212136; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 536918). 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 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.

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Jan 22, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 22, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP2, PM2, PS4_moderate

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.7	L
PhyloP100		-0.28
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.72
Sift4G	Benign	0.11	T
Polyphen		0.0010	B
Vest4		0.88
MutPred		0.84		Loss of ubiquitination at K86 (P = 0.1647)
MVP		1.0
ClinPred		0.88	D
GERP RS		-0.63
Varity_R		0.79
gMVP		0.89
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs1254836237; hg19: chr10-90707027;