rs771260546
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_001103.4(ACTN2):c.745G>A(p.Val249Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
ACTN2
NM_001103.4 missense
NM_001103.4 missense
Scores
6
1
7
Clinical Significance
Conservation
PhyloP100: 8.13
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_benign. Variant got -5 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.35953063).
BS2
?
High AC in GnomAdExome4 at 26 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.745G>A | p.Val249Ile | missense_variant | 8/21 | ENST00000366578.6 | |
ACTN2 | NM_001278343.2 | c.783+1164G>A | intron_variant | ||||
ACTN2 | NR_184402.1 | n.1006G>A | non_coding_transcript_exon_variant | 9/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.745G>A | p.Val249Ile | missense_variant | 8/21 | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251468Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135910
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727242
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74328
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 19, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | ACTN2: PM2 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 11, 2018 | The p.Val249Ile variant in ACTN2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.0036% (4/111696) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It has also been repor ted in ClinVar (Variant ID # 264452). Computational prediction tools and conserv ation analysis suggest that this variant may impact the protein, though this inf ormation is not predictive enough to determine pathogenicity. In summary, the cl inical significance of the p.Val249Ile variant is uncertain. ACMG/AMP Criteria a pplied: PM2, PP3. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 19, 2019 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 12, 2019 | The p.V249I variant (also known as c.745G>A), located in coding exon 8 of the ACTN2 gene, results from a G to A substitution at nucleotide position 745. The valine at codon 249 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
T
Sift4G
Pathogenic
D;T
Polyphen
0.78
.;P
Vest4
MVP
MPC
1.8
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at