rs1555123639
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000256.3(MYBPC3):āc.296A>Cā(p.Lys99Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,341,012 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.296A>C | p.Lys99Thr | missense_variant | 3/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.296A>C | p.Lys99Thr | missense_variant | 3/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.296A>C | p.Lys99Thr | missense_variant | 3/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.296A>C | p.Lys99Thr | missense_variant, NMD_transcript_variant | 3/27 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000201 AC: 2AN: 99426Hom.: 1 AF XY: 0.0000364 AC XY: 2AN XY: 54898
GnomAD4 exome AF: 0.00000149 AC: 2AN: 1341012Hom.: 1 Cov.: 31 AF XY: 0.00000303 AC XY: 2AN XY: 660896
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 11, 2017 | The p.Lys99Thr variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy. Data from large population studies is insufficient to asse ss the frequency of this variant. This variant was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary , the clinical significance of the p.Lys99Thr variant is uncertain. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 26, 2019 | 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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 517237). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces lysine with threonine at codon 99 of the MYBPC3 protein (p.Lys99Thr). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and threonine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at