1-236747683-G-A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_001103.4(ACTN2):c.1423G>A(p.Asp475Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,613,920 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D475D) has been classified as Likely benign.
Frequency
Consequence
NM_001103.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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ACTN2 | NM_001103.4 | c.1423G>A | p.Asp475Asn | missense_variant | Exon 13 of 21 | ENST00000366578.6 | NP_001094.1 | |
ACTN2 | NM_001278343.2 | c.1423G>A | p.Asp475Asn | missense_variant | Exon 13 of 21 | NP_001265272.1 | ||
ACTN2 | NR_184402.1 | n.1795G>A | non_coding_transcript_exon_variant | Exon 15 of 23 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00372 AC: 566AN: 152116Hom.: 25 Cov.: 32
GnomAD3 exomes AF: 0.00778 AC: 1956AN: 251376Hom.: 97 AF XY: 0.00745 AC XY: 1012AN XY: 135876
GnomAD4 exome AF: 0.00273 AC: 3995AN: 1461686Hom.: 163 Cov.: 31 AF XY: 0.00275 AC XY: 1999AN XY: 727162
GnomAD4 genome AF: 0.00370 AC: 564AN: 152234Hom.: 24 Cov.: 32 AF XY: 0.00408 AC XY: 304AN XY: 74438
ClinVar
Submissions by phenotype
not specified Benign:7
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. -
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not provided Benign:3
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Variant summary: The ACTN2 c.1423G>A (p.Asp475Asn) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 861/119100 control chromosomes (including 45 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.090941 (777/8544). This frequency is about 3638 times the estimated maximal expected allele frequency of a pathogenic ACTN2 variant (0.000025), strong evidence that this is a common benign polymorphism found primarily in the populations of East Asian. In addition, multiple clinical diagnostic laboratories have classified this variant as benign. This variant has also been found in patients with HCM, however, in one patient from a family another variant (TNNI3 p.Arg145Gly) was found to explain the phenotype (Zhao_2015). Taken together, this variant is classified as Benign. -
Cardiomyopathy Benign:1
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Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA Benign:1
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Dilated cardiomyopathy 1AA Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Dilated cardiomyopathy 1AA;C5203349:Myopathy, distal, 6, adult-onset, autosomal dominant;C5231445:Myopathy, congenital, with structured cores and z-line abnormalities Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at