rs146164600
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2
The NM_001103.4(ACTN2):c.1930G>A(p.Ala644Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,613,984 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). Synonymous variant affecting the same amino acid position (i.e. A644A) has been classified as Benign.
Frequency
Consequence
NM_001103.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.1930G>A | p.Ala644Thr | missense_variant | 16/21 | ENST00000366578.6 | |
ACTN2 | NM_001278343.2 | c.1930G>A | p.Ala644Thr | missense_variant | 16/21 | ||
ACTN2 | NR_184402.1 | n.2302G>A | non_coding_transcript_exon_variant | 18/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.1930G>A | p.Ala644Thr | missense_variant | 16/21 | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152220Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000163 AC: 41AN: 251014Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135770
GnomAD4 exome AF: 0.000148 AC: 216AN: 1461764Hom.: 0 Cov.: 36 AF XY: 0.000151 AC XY: 110AN XY: 727182
GnomAD4 genome AF: 0.000138 AC: 21AN: 152220Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10AN XY: 74376
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 08, 2022 | BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2023 | Reported in patients with cardiomyopathy in the published literature (Chiu et al., 2010; Pugh et al., 2014; Lombardi et al., 2020; Sepp et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24503780, 32527005, 20022194, 35626289, 28771489) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 14, 2010 | The Ala644Thr variant has been reported in one proband with HCM. Although the va riant was absent from 520 control chromosomes, the authors classified it as ?ben ign? due to its presence in unaffected family members. However, no clinical deta ils are available (Chiu 2009). Alanine (Ala) at position 644 is not completely c onserved across different species (frog carries a glycine), reducing the likelih ood that a change is pathogenic. In addition, this individual has a diagnosis o f DCM, while the proband tested by Chiu 2009 was diagnosed with HCM. Provided th at the diagnosis of primary DCM has been firmly established, the presence of a v ariant in HCM and DCM probands reduces the likelihood that it is pathogenic as t he two cardiomyopathies are caused by different defects at the cellular level. In summary, the clinical significance of this variant cannot be determined witho ut additional studies. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 02, 2021 | - - |
Dilated cardiomyopathy 1AA Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Dilated cardiomyopathy 1AA;C5203349:Myopathy, distal, 6, adult-onset, autosomal dominant;C5231445:Myopathy, congenital, with structured cores and z-line abnormalities Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 12, 2021 | - - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Oct 11, 2016 | - - |
Tetralogy of Fallot Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Feb 27, 2017 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 13, 2022 | The c.1930G>A (p.A644T) alteration is located in exon 16 (coding exon 16) of the ACTN2 gene. This alteration results from a G to A substitution at nucleotide position 1930, causing the alanine (A) at amino acid position 644 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 | Invitae | Jan 27, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at