rs138061447
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_016599.5(MYOZ2):c.302C>A(p.Ser101Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,692 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S101S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_016599.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYOZ2 | NM_016599.5 | c.302C>A | p.Ser101Ter | stop_gained | 4/6 | ENST00000307128.6 | |
MYOZ2 | XM_006714234.5 | c.302C>A | p.Ser101Ter | stop_gained | 4/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYOZ2 | ENST00000307128.6 | c.302C>A | p.Ser101Ter | stop_gained | 4/6 | 1 | NM_016599.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 151898Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251266Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135786
GnomAD4 exome AF: 0.0000670 AC: 98AN: 1461794Hom.: 0 Cov.: 35 AF XY: 0.0000688 AC XY: 50AN XY: 727200
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 151898Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74170
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Sep 07, 2021 | - - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2014 | p.Ser101Stop (TCG>TAG): c.302 C>A in exon 4 of the MYOZ2 gene (NM_016599.4). A variant of unknown significance has been identified in the MYOZ2 gene. The S101X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. S101X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. However, the S101X sequence change in the MYOZ2 gene was reported as a variant of unknown significance (Ng et al., 2013). S101X was reported in one individual from 870 participants not selected for a clinical phenotype or family history of arrhythmia or cardiomyopathy, who underwent whole exome sequencing as part of the ClinSeq study (Ng et al., 2013). The authors piloted a method to identify incidental results in cardiomyopathy and arrhythmia-associated alleles and provided interpretation for these variants (Ng et al., 2013). The S101X variant was classified as a variant of unknown significance given that no loss-of-function mutations have been reported in the MYOZ2 gene in association with cardiomyopathy (Ng et al., 2013).Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in CARDIOMYOPATHY - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 25, 2020 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 03, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 191742). This premature translational stop signal has been observed in individual(s) with left ventricular hypertrophy (PMID: 31534214). This variant is present in population databases (rs138061447, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Ser101*) in the MYOZ2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYOZ2 cause disease. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 29, 2019 | The p.S101* variant (also known as c.302C>A), located in coding exon 3 of the MYOZ2 gene, results from a C to A substitution at nucleotide position 302. This changes the amino acid from a serine to a stop codon within coding exon 3. This alteration has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of MYOZ2 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hypertrophic cardiomyopathy 16 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 20, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at