chr11-47333624-G-A
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000256.3(MYBPC3):c.3123C>T(p.Gly1041Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,606,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G1041G) has been classified as Likely benign.
Frequency
Consequence
NM_000256.3 synonymous
Scores
Clinical Significance
Conservation
Publications
- hypertrophic cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- hypertrophic cardiomyopathy 4Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
- left ventricular noncompaction 10Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- atrial fibrillationInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.3123C>T | p.Gly1041Gly | synonymous_variant | Exon 29 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.3123C>T | p.Gly1041Gly | synonymous_variant | Exon 28 of 34 | 5 | ENSP00000382193.2 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152252Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000123 AC: 3AN: 243712 AF XY: 0.00000753 show subpopulations
GnomAD4 exome AF: 0.0000220 AC: 32AN: 1453800Hom.: 0 Cov.: 33 AF XY: 0.0000304 AC XY: 22AN XY: 723640 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74382 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
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This synonymous variant causes a C>T nucleotide change in exon 29 of the MYBPC3 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional mini-gene assay has shown that this variant is not likely to have a significant impact on splicing (PMID: 28679633). This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 4/275114 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:2
Reported in the published literature in a patient with cardiomyopathy without detailed clinical information and reported as uncertain significance (PMID: 28679633); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 28679633) -
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Hypertrophic cardiomyopathy Uncertain:2
This sequence change affects codon 1041 of the MYBPC3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYBPC3 protein. This variant is present in population databases (rs374626656, gnomAD 0.009%). This variant has been observed in individual(s) with clinical features of MYBPC3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 181001). 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. -
The MYBPC3 c.3123C>T variant is classified as VUS (PM2_Supporting, PP3) This MYBPC3 c.3123C>T variant is a synonymous (silent) variant located in exon 29/35. The variant is rare in population databases (gnomAD allele frequency = 0.0059%; 9 het and 0 hom) (PM2_Supporting) and is reported in at least 5 individuals with Hypertrophic Cardiomyopathy (ClinVar). Computational splicing tools support a deleterious effect on the gene or gene product through the predicted gain of a donor splice site (PMID#28679633)(PP3). The variant has been reported in dbSNP (rs374626656), is reported as ?disease causing in the HGMD database (CS179892) and is reported as uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 181001). -
Cardiovascular phenotype Uncertain:1
The c.3123C>T variant (also known as p.G1041G) is located in coding exon 29 of the MYBPC3 gene. This variant results from a C to T substitution at nucleotide position 3123. This nucleotide substitution does not change the glycine at codon 1041. A minigene study indicated that this variant may not have a significant impact on splicing (Ito K et al. Proc Natl Acad Sci U S A, 2017 Jul;114:7689-7694). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. 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