chr11-47333960-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000256.3(MYBPC3):c.2956A>G(p.Lys986Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,432,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2956A>G | p.Lys986Glu | missense_variant | Exon 28 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.2956A>G | p.Lys986Glu | missense_variant | Exon 27 of 34 | 5 | ENSP00000382193.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000492 AC: 1AN: 203302Hom.: 0 AF XY: 0.00000911 AC XY: 1AN XY: 109746
GnomAD4 exome AF: 0.0000161 AC: 23AN: 1432802Hom.: 0 Cov.: 33 AF XY: 0.0000155 AC XY: 11AN XY: 710014
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:1
The p.Lys986Glu variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy. Data from large population studies are insufficient to de termine its frequency. Lysine (Lys) at position 986 is not conserved in mammals or evolutionarily distant species and the change to glutamic acid (Glu) was pre dicted to be benign using a computational tool clinically validated by our labor atory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, the clinical significance of the p.Lys986Glu variant is uncertain. -
Dilated cardiomyopathy 1A Uncertain:1
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Hypertrophic cardiomyopathy Uncertain:1
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 986 of the MYBPC3 protein (p.Lys986Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 228868). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.K986E variant (also known as c.2956A>G), located in coding exon 28 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 2956. The lysine at codon 986 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Harper AR et al. Nat Genet, 2021 Feb;53:135-142). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at