rs794728964
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_001103.4(ACTN2):c.784-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001103.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.784-2A>G | splice_acceptor_variant, intron_variant | Intron 8 of 20 | ENST00000366578.6 | NP_001094.1 | ||
ACTN2 | NM_001278343.2 | c.784-2A>G | splice_acceptor_variant, intron_variant | Intron 8 of 20 | NP_001265272.1 | |||
ACTN2 | NR_184402.1 | n.1156-2A>G | splice_acceptor_variant, intron_variant | Intron 10 of 22 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 28
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1444974Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 718854
GnomAD4 genome Cov.: 28
ClinVar
Submissions by phenotype
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Uncertain:1
The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ACTN2 cause disease. Therefore, this variant has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ACTN2-related disease. ClinVar contains an entry for this variant (Variation ID: 201633). This sequence change affects an acceptor splice site in intron 8 of the ACTN2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -
not provided Uncertain:1
Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant in a gene for which loss-of-function is not a known mechanism of disease; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 201633; Landrum et al., 2016) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at