rs201920417
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_001103.4(ACTN2):c.-3G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000894 in 1,555,236 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: 𝑓 0.000086 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000090 ( 0 hom. )
Consequence
ACTN2
NM_001103.4 5_prime_UTR
NM_001103.4 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.35
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 Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
?
Variant 1-236686671-G-T is Benign according to our data. Variant chr1-236686671-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162723.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
BS2
?
High AC in GnomAd4 at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.-3G>T | 5_prime_UTR_variant | 1/21 | ENST00000366578.6 | ||
ACTN2 | NM_001278343.2 | c.-3G>T | 5_prime_UTR_variant | 1/21 | |||
ACTN2 | NR_184402.1 | n.173G>T | non_coding_transcript_exon_variant | 1/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.-3G>T | 5_prime_UTR_variant | 1/21 | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000857 AC: 13AN: 151688Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000170 AC: 36AN: 212092Hom.: 0 AF XY: 0.000198 AC XY: 23AN XY: 116442
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GnomAD4 exome AF: 0.0000898 AC: 126AN: 1403548Hom.: 0 Cov.: 31 AF XY: 0.0000888 AC XY: 62AN XY: 698366
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GnomAD4 genome ? AF: 0.0000857 AC: 13AN: 151688Hom.: 0 Cov.: 31 AF XY: 0.0000945 AC XY: 7AN XY: 74080
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
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 | Mar 24, 2015 | The c.-3G>T variant in ACTN2 has been previously identified by our laboratory in 2 Ashkenazi Jewish adults with HCM. It has also been identified in 10/64028 Eur opean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; dbSNP rs201920417). This variant is located in the 5' UTR and is pa rt of the translation initiation (Kozak) sequence, but its effect on translation is unknown. In summary, the clinical significance of the c.-3G>T variant is unc ertain. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 11, 2020 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2023 | See Variant Classification Assertion Criteria. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 25, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
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DANN
Benign
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