11-47337495-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_000256.3(MYBPC3):​c.2498C>G​(p.Ala833Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A833T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

2
10
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.60
Variant links:
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 7 ACMG points.

PM1
In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) 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 chr11-47337496-C-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYBPC3NM_000256.3 linkc.2498C>G p.Ala833Gly missense_variant Exon 25 of 35 ENST00000545968.6 NP_000247.2 Q14896-1A5YM48

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYBPC3ENST00000545968.6 linkc.2498C>G p.Ala833Gly missense_variant Exon 25 of 35 5 NM_000256.3 ENSP00000442795.1 Q14896-1
MYBPC3ENST00000399249.6 linkc.2498C>G p.Ala833Gly missense_variant Exon 24 of 34 5 ENSP00000382193.2 A8MXZ9
MYBPC3ENST00000544791.1 linkn.*3C>G non_coding_transcript_exon_variant Exon 25 of 27 5 ENSP00000444259.1 F5GZR4
MYBPC3ENST00000544791.1 linkn.*3C>G 3_prime_UTR_variant Exon 25 of 27 5 ENSP00000444259.1 F5GZR4

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461678
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727130
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
CardioboostCm
Benign
0.042
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.070
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
T;T;T
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.80
D;D;D
MetaSVM
Benign
-0.32
T
MutationAssessor
Pathogenic
3.4
M;.;.
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-2.3
N;.;N
REVEL
Benign
0.22
Sift
Benign
0.036
D;.;D
Sift4G
Benign
0.15
T;T;T
Vest4
0.68
MVP
0.91
MPC
0.82
ClinPred
0.99
D
GERP RS
4.6
Varity_R
0.70
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-47359046; API