4-119158118-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_016599.5(MYOZ2):c.343C>T(p.Arg115*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,928 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 (★★). 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
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152108Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251336Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135830
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461820Hom.: 0 Cov.: 35 AF XY: 0.0000206 AC XY: 15AN XY: 727214
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152108Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74280
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:1
Heterozygous variant NM_016599:c.343C>T (p.Arg115*) in the MYOZ2 gene was found on WES data in male proband (54 y.o., Caucasian) with Cardiomyopathy, unspecified (ICD-10 I42.9) and Bradycardia. An additional rare candidate variant NM_001194:c.449G>T (p.Gly150Val) in the HCN2 gene (Class III of pathogenicity) was found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.00005306 (Date of access 12-07-2023). Clinvar contains entry on this variant (Variation ID: 412240). This variant has been reported in 1 patient with Cardiomyopathy with complex genotype (PMID: 31110529) and classified as Class III of pathogenicity (VUS). In accordance with ACMG(2015) this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: PM2. -
not provided Uncertain:1
The patient had genetic testing with a comprehensive cardiomyopathy and arrhythmia panel. The test included a total of 35 genes associated with various hereditary cardiomyopathies and arrhythmias. Analysis included sequencing with analysis for exonic duplications and deletions (note that deletions and duplications were called based on depth of coverage). Results reported on May 19, 2016 showed that a variant was found (see report below): - p.Arg115* (c.343C>T) in the MYOZ2 gene (NM_016599.4) The lab classifies this variant as a variant of unknown significance. Given insufficient case data we consider this variant a variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has not been reported in individuals with cardiomyopathy before. There variant has been previously reported in six people in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of June 2, 2016). This has a population frequency of about 1/10,000 individuals in that dataset. There are an additional four individuals with variants at that position (p.Arg115Gln and p.Arg115Arg). -
Hypertrophic cardiomyopathy Uncertain:1
This sequence change creates a premature translational stop signal (p.Arg115*) 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. This variant is present in population databases (rs374655743, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 31110529). ClinVar contains an entry for this variant (Variation ID: 412240). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Cardiovascular phenotype Uncertain:1
The p.R115* variant (also known as c.343C>T), located in coding exon 3 of the MYOZ2 gene, results from a C to T substitution at nucleotide position 343. This changes the amino acid from an arginine to a stop codon within coding exon 3. This alteration is expected to result in 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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at