14-68874953-G-A
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001130004.2(ACTN1):c.2651C>T(p.Ala884Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000892 in 1,613,580 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000089 ( 0 hom. )
Consequence
ACTN1
NM_001130004.2 missense
NM_001130004.2 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 5.66
Genes affected
ACTN1 (HGNC:163): (actinin alpha 1) 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 nonmuscle, cytoskeletal, alpha actinin isoform and maps to the same site as the structurally similar erythroid beta spectrin gene. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTN1. . Gene score misZ: 3.3621 (greater than the threshold 3.09). Trascript score misZ: 5.1933 (greater than threshold 3.09). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. GenCC has associacion of the gene with autosomal dominant macrothrombocytopenia, platelet-type bleeding disorder 15.
BP4
Computational evidence support a benign effect (MetaRNN=0.16737136).
BS2
High AC in GnomAd4 at 14 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152196Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000960 AC: 24AN: 250100Hom.: 0 AF XY: 0.0000886 AC XY: 12AN XY: 135508
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GnomAD4 exome AF: 0.0000890 AC: 130AN: 1461384Hom.: 0 Cov.: 31 AF XY: 0.0000770 AC XY: 56AN XY: 726996
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GnomAD4 genome AF: 0.0000920 AC: 14AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74342
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 23, 2021 | 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 | Labcorp Genetics (formerly Invitae), Labcorp | Sep 08, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1326697). This variant has not been reported in the literature in individuals affected with ACTN1-related conditions. This variant is present in population databases (rs199901015, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 884 of the ACTN1 protein (p.Ala884Val). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
T;.;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Benign
Sift
Benign
D;D;D;D;D
Sift4G
Benign
T;T;T;T;T
Polyphen
P;.;D;.;.
Vest4
MVP
MPC
0.20
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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