chr14-68874992-C-T
Variant names:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_001130004.2(ACTN1):c.2612G>A(p.Arg871His) variant causes a missense change. The variant allele was found at a frequency of 0.0000465 in 1,613,584 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 0.00025 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
ACTN1
NM_001130004.2 missense
NM_001130004.2 missense
Scores
5
8
6
Clinical Significance
Conservation
PhyloP100: 6.11
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 Benign. Variant got -10 ACMG points.
PP2
Missense variant in the ACTN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 3.3621 (above the threshold of 3.09). Trascript score misZ: 5.1933 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant macrothrombocytopenia, platelet-type bleeding disorder 15.
BP4
Computational evidence support a benign effect (MetaRNN=0.1845968).
BP6
Variant 14-68874992-C-T is Benign according to our data. Variant chr14-68874992-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 426733.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000249 (38/152312) while in subpopulation AFR AF= 0.00089 (37/41570). AF 95% confidence interval is 0.000664. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 38 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000250 AC: 38AN: 152194Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000841 AC: 21AN: 249688Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135420
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GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461272Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 726956
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GnomAD4 genome AF: 0.000249 AC: 38AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15AN XY: 74482
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 23, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2017 | The R871H variant in the ACTN1 gene has not been reported previously as a germline pathogenic variant, nor as a benign variant, to our knowledge. The R871H variant is observed in 9/9776 (0.09%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R871H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R871H as a variant of uncertain significance. - |
ACTN1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 13, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T;.;.;T;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;.;D;.;.
Vest4
MVP
MPC
0.051
ClinPred
D
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