rs397516568

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

Scores

3
13
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.78
Variant links:
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
ACTN2NM_001103.4 linkuse as main transcriptc.1411C>G p.Leu471Val missense_variant 13/21 ENST00000366578.6 NP_001094.1 P35609-1
ACTN2NM_001278343.2 linkuse as main transcriptc.1411C>G p.Leu471Val missense_variant 13/21 NP_001265272.1 P35609-2
ACTN2NR_184402.1 linkuse as main transcriptn.1783C>G non_coding_transcript_exon_variant 15/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACTN2ENST00000366578.6 linkuse as main transcriptc.1411C>G p.Leu471Val missense_variant 13/211 NM_001103.4 ENSP00000355537.4 P35609-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 09, 2012Variant 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Uncertain
0.056
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
.;.;D
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Benign
0.040
D
MetaRNN
Uncertain
0.54
D;D;D
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Uncertain
2.7
.;M;M
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-2.7
.;D;D
REVEL
Uncertain
0.31
Sift
Uncertain
0.0040
.;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.54
.;.;P
Vest4
0.69
MutPred
0.45
.;Loss of stability (P = 0.0691);Loss of stability (P = 0.0691);
MVP
0.57
MPC
0.41
ClinPred
0.97
D
GERP RS
3.9
Varity_R
0.84
gMVP
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397516568; hg19: chr1-236910971; API