11-47347891-C-G

Position:

• chr11-47347891-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000256.3(MYBPC3):​c.787G>C​(p.Gly263Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.44

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.787G>C	p.Gly263Arg	missense_variant	7/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.787G>C	p.Gly263Arg	missense_variant	7/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.787G>C	p.Gly263Arg	missense_variant	7/34	5		A2
MYBPC3	ENST00000544791.1	c.787G>C	p.Gly263Arg	missense_variant, NMD_transcript_variant	7/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
CardioboostCm	Benign	0.0030
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.47	P;.;.
Vest4		0.83
MutPred		0.79		Loss of catalytic residue at G263 (P = 0.0382);Loss of catalytic residue at G263 (P = 0.0382);Loss of catalytic residue at G263 (P = 0.0382);
MVP		0.79
MPC		0.60
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.13
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs373730381; hg19: chr11-47369442;