rs397516568
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001103.4(ACTN2):c.1411C>G(p.Leu471Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L471P) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
ACTN2
NM_001103.4 missense
NM_001103.4 missense
Scores
3
13
3
Clinical Significance
Conservation
PhyloP100: 2.78
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.1411C>G | p.Leu471Val | missense_variant | 13/21 | ENST00000366578.6 | NP_001094.1 | |
ACTN2 | NM_001278343.2 | c.1411C>G | p.Leu471Val | missense_variant | 13/21 | NP_001265272.1 | ||
ACTN2 | NR_184402.1 | n.1783C>G | non_coding_transcript_exon_variant | 15/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.1411C>G | p.Leu471Val | missense_variant | 13/21 | 1 | NM_001103.4 | ENSP00000355537.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 09, 2012 | Variant classified as Uncertain Significance - Favor Pathogenic. The Leu471Val v ariant in ACTN2 has not been reported in the literature nor previously identifie d by our laboratory. This variant was absent from 2 very large and broad popula tions (European and African American) screened by the NHLBI Exome Sequencing Pro ject (http://evs.gs.washington.edu/EVS). This low frequency is consistent with a disease causing role but insufficient to establish this with confidence. Comput ational analyses (biochemical amino acid properties, conservation, AlignGVGD, Po lyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Although this data supports that the Leu471Val variant may be pathogenic, additional studies a re needed to fully assess its clinical significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
.;M;M
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;D;D
REVEL
Uncertain
Sift
Uncertain
.;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
0.54
.;.;P
Vest4
MutPred
0.45
.;Loss of stability (P = 0.0691);Loss of stability (P = 0.0691);
MVP
MPC
0.41
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at