rs730880575
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_000256.3(MYBPC3):āc.94G>Cā(p.Glu32Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E32K) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 missense
NM_000256.3 missense
Scores
1
12
7
Clinical Significance
Conservation
PhyloP100: 4.58
Genes affected
MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a strand (size 5) in uniprot entity MYPC3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000256.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-47351437-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.94G>C | p.Glu32Gln | missense_variant | 2/35 | ENST00000545968.6 | NP_000247.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.94G>C | p.Glu32Gln | missense_variant | 2/35 | 5 | NM_000256.3 | ENSP00000442795 | P4 | |
MYBPC3 | ENST00000399249.6 | c.94G>C | p.Glu32Gln | missense_variant | 2/34 | 5 | ENSP00000382193 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.94G>C | p.Glu32Gln | missense_variant, NMD_transcript_variant | 2/27 | 5 | ENSP00000444259 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000416 AC: 1AN: 240644Hom.: 0 AF XY: 0.00000761 AC XY: 1AN XY: 131328
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1456626Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1AN XY: 724220
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 23, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 32 of the MYBPC3 protein (p.Glu32Gln). This variant is present in population databases (rs730880575, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0314);Gain of MoRF binding (P = 0.0314);Gain of MoRF binding (P = 0.0314);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at