rs536297856
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2
The NM_001103.4(ACTN2):c.2668G>A(p.Gly890Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000048 ( 0 hom. )
Consequence
ACTN2
NM_001103.4 missense
NM_001103.4 missense
Scores
11
2
2
Clinical Significance
Conservation
PhyloP100: 9.81
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 -3 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.885
BP6
?
Variant 1-236762602-G-A is Benign according to our data. Variant chr1-236762602-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573987.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
BS2
?
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.2668G>A | p.Gly890Arg | missense_variant | 21/21 | ENST00000366578.6 | |
ACTN2 | NM_001278343.2 | c.2668G>A | p.Gly890Arg | missense_variant | 21/21 | ||
ACTN2 | NR_184402.1 | n.3040G>A | non_coding_transcript_exon_variant | 23/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.2668G>A | p.Gly890Arg | missense_variant | 21/21 | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251106Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135736
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GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461792Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37AN XY: 727202
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74438
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2018 | The p.G890R variant (also known as c.2668G>A), located in coding exon 21 of the ACTN2 gene, results from a G to A substitution at nucleotide position 2668. The glycine at codon 890 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
REVEL
Pathogenic
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;.;D
Vest4
MutPred
0.80
.;Gain of solvent accessibility (P = 0.0306);Gain of solvent accessibility (P = 0.0306);
MVP
MPC
0.90
ClinPred
D
GERP RS
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