rs369300885

Variant names:

• chr11-47348514-C-A
• rs369300885
• NM_000256.3:c.682G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-47348514-C-A
• chr11-47348514-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000256.3(MYBPC3):​c.682G>T​(p.Asp228Tyr) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D228E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 0 publications found

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]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.682G>T	p.Asp228Tyr	missense_variant	Exon 6 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.682G>T	p.Asp228Tyr	missense_variant	Exon 6 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.682G>T	p.Asp228Tyr	missense_variant	Exon 6 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.682G>T		non_coding_transcript_exon_variant	Exon 6 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
CardioboostCm	Benign	0.010
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.90	L;.;.
PhyloP100		2.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.023	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.98	D;.;.
Vest4		0.54
MutPred		0.68		Gain of phosphorylation at D228 (P = 0.1274);Gain of phosphorylation at D228 (P = 0.1274);Gain of phosphorylation at D228 (P = 0.1274);
MVP		0.88
MPC		0.83
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.25
gMVP		0.69
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs369300885; hg19: chr11-47370065;