rs139489232
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2
The NM_001103.4(ACTN2):c.690T>A(p.Asp230Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,613,110 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D230V) has been classified as Uncertain significance.
Frequency
Consequence
NM_001103.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.690T>A | p.Asp230Glu | missense_variant | 7/21 | ENST00000366578.6 | |
ACTN2 | NM_001278343.2 | c.690T>A | p.Asp230Glu | missense_variant | 7/21 | ||
ACTN2 | NR_184402.1 | n.865T>A | non_coding_transcript_exon_variant | 7/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.690T>A | p.Asp230Glu | missense_variant | 7/21 | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000985 AC: 15AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000115 AC: 29AN: 251362Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135852
GnomAD4 exome AF: 0.000198 AC: 289AN: 1460750Hom.: 0 Cov.: 29 AF XY: 0.000173 AC XY: 126AN XY: 726754
GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152360Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74512
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Apr 14, 2016 | - - |
not specified Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 18, 2017 | The D230E variant of uncertain significance in the ACTN2 gene has not been published as apathogenic variant, nor has it been reported as a benign variant to our knowledge. The D230E variant was not observedwith any significant frequency in the NHLBI Exome Sequencing Project or in the Exome AggregationConsortium (ExAC). This substitution occurs at a position that is conserved across species and in silicoanalysis predicts this variant is probably damaging to the protein structure/function. However, theD230E variant is a conservative amino acid substitution, which is less likely to impact secondaryprotein structure as these residues share similar properties.Therefore, based on the currently available information, it is unclear whether this variant ispathogenic or benign. This result cannot be interpreted for diagnosis or used for family memberscreening at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 25, 2014 | The p.Asp230Glu variant in ACTN2 has been previously identified by our laborator y in 1 Caucasian adult with HCM. This variant has been identified in 11/67686 of Non-Finnish European chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs139489232). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, thou gh this information is not predictive enough to determine pathogenicity. In summ ary, the clinical significance of the p.Asp230Glu variant is uncertain. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 21, 2023 | Variant summary: ACTN2 c.690T>A (p.Asp230Glu) results in a conservative amino acid change located in the Calponin homology domain (IPR001715) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251362 control chromosomes. The observed variant frequency is approximately 4.61 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.690T>A has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Walsh_2017, Mazzarotto_2020) but it was also reported in healthy control(s) (e.g. Mazzarotto_2020). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign. - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Dec 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 26, 2019 | - - |
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 | Sep 10, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2020 | The c.690T>A (p.D230E) alteration is located in exon 7 (coding exon 7) of the ACTN2 gene. This alteration results from a T to A substitution at nucleotide position 690, causing the aspartic acid (D) at amino acid position 230 to be replaced by a glutamic acid (E). 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 04, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at