rs150182164
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_001103.4(ACTN2):c.441G>A(p.Ser147=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,612,532 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.0010 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
ACTN2
NM_001103.4 synonymous
NM_001103.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.834
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.39).
BP6
?
Variant 1-236720184-G-A is Benign according to our data. Variant chr1-236720184-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236720184-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=0.834 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.001 (153/152294) while in subpopulation AFR AF= 0.00347 (144/41556). AF 95% confidence interval is 0.003. There are 0 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 153 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACTN2 | NM_001103.4 | c.441G>A | p.Ser147= | synonymous_variant | 4/21 | ENST00000366578.6 | |
ACTN2 | NM_001278343.2 | c.441G>A | p.Ser147= | synonymous_variant | 4/21 | ||
ACTN2 | NR_184402.1 | n.616G>A | non_coding_transcript_exon_variant | 4/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACTN2 | ENST00000366578.6 | c.441G>A | p.Ser147= | synonymous_variant | 4/21 | 1 | NM_001103.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00101 AC: 153AN: 152176Hom.: 0 Cov.: 34
GnomAD3 genomes
?
AF:
AC:
153
AN:
152176
Hom.:
Cov.:
34
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000322 AC: 81AN: 251326Hom.: 0 AF XY: 0.000317 AC XY: 43AN XY: 135826
GnomAD3 exomes
AF:
AC:
81
AN:
251326
Hom.:
AF XY:
AC XY:
43
AN XY:
135826
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000127 AC: 186AN: 1460238Hom.: 0 Cov.: 33 AF XY: 0.000128 AC XY: 93AN XY: 726598
GnomAD4 exome
AF:
AC:
186
AN:
1460238
Hom.:
Cov.:
33
AF XY:
AC XY:
93
AN XY:
726598
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00100 AC: 153AN: 152294Hom.: 0 Cov.: 34 AF XY: 0.00107 AC XY: 80AN XY: 74476
GnomAD4 genome
?
AF:
AC:
153
AN:
152294
Hom.:
Cov.:
34
AF XY:
AC XY:
80
AN XY:
74476
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
2
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 26, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2012 | p.Ser147Ser in Exon 04 of ACTN2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 0.4% (14/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs150182164). - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 04, 2016 | - - |
Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 15, 2016 | Variant summary: Variant Summary: The c.441G.A (p.Ser147=) in ACTN2 gene is a synonymous change that involves a non-conserved nucleotide with a prediction of being a "disease-causing" by mutation taster. 4/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at an overall allele frequency of 0.036% (44/121320 chrs tested), mainly in individuals of African descent (0.32%; 33/10388 chrs tested). The observed frequency exceeds the maximum expected allele frequency for a pathogenic ACTN2 variant (0.0025%), suggesting that it is a common polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via published reports. Variant was identified in one individual undergoing genetic screening for CMYO panel, who tested positive for a known pathogenic variant in TTR. Lastly, the variant has been reported as Benign by a reputable database/clinical laboratory. Taken together, the variant was classified as Benign. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 26, 2016 | 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
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at