rs397516573
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001103.4(ACTN2):āc.2306A>Cā(p.Lys769Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,216 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: š 0.0000066 ( 0 hom., cov: 32)
Consequence
ACTN2
NM_001103.4 missense
NM_001103.4 missense
Scores
1
13
5
Clinical Significance
Conservation
PhyloP100: 4.16
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 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.26223892).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.2306A>C | p.Lys769Thr | missense_variant | 19/21 | ENST00000366578.6 | NP_001094.1 | |
ACTN2 | NM_001278343.2 | c.2306A>C | p.Lys769Thr | missense_variant | 19/21 | NP_001265272.1 | ||
ACTN2 | NR_184402.1 | n.2678A>C | non_coding_transcript_exon_variant | 21/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.2306A>C | p.Lys769Thr | missense_variant | 19/21 | 1 | NM_001103.4 | ENSP00000355537.4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 32
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GnomAD4 exome Cov.: 31
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74362
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
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 | Sep 19, 2012 | The Lys769Thr variant in ACTN2 has not been reported in the literature nor previ ously identified by our laboratory. It was detected by our laboratory in 1 infan t with DCM (this individual). This individual was of African American ancestry and the variant was absent from >4,000 African American chromosomes screened by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/). This low frequency supports a role in disease. However, the affected amino acid is not well conserved in evolution, suggesting that a change may be tolerated. Other co mputational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, a nd SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of th is variant. - |
Dilated cardiomyopathy 1AA Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | KardioGenetik, Herz- und Diabeteszentrum NRW | Nov 16, 2023 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 14, 2020 | The c.2306A>C (p.K769T) alteration is located in exon 19 (coding exon 19) of the ACTN2 gene. This alteration results from a A to C substitution at nucleotide position 2306, causing the lysine (K) at amino acid position 769 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 02, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
.;M;M
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;N
REVEL
Uncertain
Sift
Uncertain
.;D;D
Sift4G
Uncertain
D;T;T
Polyphen
0.035
.;.;B
Vest4
MutPred
0.39
.;Loss of ubiquitination at K769 (P = 0.0074);Loss of ubiquitination at K769 (P = 0.0074);
MVP
MPC
0.30
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