chr11-47346320-C-A

Variant names:

• chr11-47346320-C-A
• NM_000256.3:c.977G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000256.3(MYBPC3):​c.977G>T​(p.Arg326Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,334 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R326Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47346320-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.977G>T	p.Arg326Leu	missense_variant	Exon 12 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.977G>T	p.Arg326Leu	missense_variant	Exon 12 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.977G>T	p.Arg326Leu	missense_variant	Exon 11 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.977G>T		non_coding_transcript_exon_variant	Exon 12 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459334 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
CardioboostCm	Benign	0.052
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;T;T
Eigen	Benign	0.066
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.3	L;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.45	B;.;.
Vest4		0.56
MutPred		0.46		Loss of disorder (P = 0.0642);Loss of disorder (P = 0.0642);Loss of disorder (P = 0.0642);
MVP		0.83
MPC		0.44
ClinPred		0.87	D
GERP RS		4.7
Varity_R		0.45
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chr11-47367871;