rs794728964
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePM2PP3_Strong
The NM_001103.4(ACTN2):c.784-2A>G variant causes a splice acceptor 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
Genomes: not found (cov: 28)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
ACTN2
NM_001103.4 splice_acceptor
NM_001103.4 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.32
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 Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.03426443 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5, offset of -31, new splice context is: gtgcgcattcccgtcgacAGagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.784-2A>G | splice_acceptor_variant | ENST00000366578.6 | |||
ACTN2 | NM_001278343.2 | c.784-2A>G | splice_acceptor_variant | ||||
ACTN2 | NR_184402.1 | n.1156-2A>G | splice_acceptor_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.784-2A>G | splice_acceptor_variant | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 28
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 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
1444974
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
718854
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 28
GnomAD4 genome
?
Cov.:
28
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2016 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2020 | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at