rs878854174
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_001103.4(ACTN2):c.2631_2632delTG(p.Ala878ThrfsTer61) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
ACTN2
NM_001103.4 frameshift
NM_001103.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.81
Genes affected
ACTN2 (HGNC:164): (actinin alpha 2) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a muscle-specific, alpha actinin isoform that is expressed in both skeletal and cardiac muscles. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0201 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ACTN2 | NM_001103.4 | c.2631_2632delTG | p.Ala878ThrfsTer61 | frameshift_variant | Exon 21 of 21 | ENST00000366578.6 | NP_001094.1 | |
| ACTN2 | NM_001278343.2 | c.2631_2632delTG | p.Ala878ThrfsTer61 | frameshift_variant | Exon 21 of 21 | NP_001265272.1 | ||
| ACTN2 | NR_184402.1 | n.3003_3004delTG | non_coding_transcript_exon_variant | Exon 23 of 23 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 10, 2016 | This sequence change deletes 2 nucleotides from exon 21 of the ACTN2 mRNA (c.2631_2632delTG), causing a frameshift at codon 878. This creates a premature translational stop signal in the last exon of the ACTN2 mRNA (p.Ala878Thrfs*61). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated ACTN2 protein. While this particular variant has not been reported in the literature, truncating variants in the last exon of genes are not necessarily deleterious (PMID: 24274751), and the clinical significance of this variant is uncertain at this time. In summary, this is a novel truncating variant with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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