rs398123280
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.2737+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000201 in 1,490,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000256.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2737+5G>A | splice_region_variant, intron_variant | Intron 26 of 34 | 5 | NM_000256.3 | ENSP00000442795.1 | |||
MYBPC3 | ENST00000399249.6 | c.2737+5G>A | splice_region_variant, intron_variant | Intron 25 of 33 | 5 | ENSP00000382193.2 | ||||
MYBPC3 | ENST00000544791.1 | n.*242+5G>A | splice_region_variant, intron_variant | Intron 26 of 26 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 30
GnomAD4 exome AF: 7.47e-7 AC: 1AN: 1338734Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 655788
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2AN XY: 74338
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
This sequence change falls in intron 26 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 30297972, 33190526; internal data). ClinVar contains an entry for this variant (Variation ID: 92690). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
This variant causes a G to A nucleotide substitution at the +5 position of intron 26 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 30297972, 32841044, 33190526; communication with external laboratories [ClinVar variation ID: 92690]). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
not provided Pathogenic:1Uncertain:1
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PVS1_moderate, PM2, PS4_moderate -
Cardiomyopathy Pathogenic:1
This variant causes a G to A nucleotide substitution at the +5 position of intron 26 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 30297972, 32841044, 33190526; communication with external laboratories [ClinVar variation ID: 92690]). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Cardiovascular phenotype Pathogenic:1
The c.2737+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 26 in the MYBPC3 gene. This alteration has been reported in multiple unrelated probands with hypertrophic cardiomyopathy (HCM) (Ho CY et al. Circulation, 2018 Oct;138:1387-1398; O'Hare BJ et al. Circ Genom Precis Med, 2020 Dec;13:e003013; GeneDx pers. comm.; Invitae pers. comm.; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at