11-47346222-C-T

Position:

• chr11-47346222-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000256.3(MYBPC3):​c.1075G>A​(p.Glu359Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1075G>A	p.Glu359Lys	missense_variant	12/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1075G>A	p.Glu359Lys	missense_variant	12/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1075G>A	p.Glu359Lys	missense_variant	11/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1075G>A		non_coding_transcript_exon_variant	12/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248970 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461590 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

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	Benign	0.31
CardioboostCm	Benign	0.0026
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.092	T;T;T
Sift4G	Benign	0.093	T;T;T
Polyphen		0.39	B;.;.
Vest4		0.55
MutPred		0.38		Gain of ubiquitination at E359 (P = 0.0325);Gain of ubiquitination at E359 (P = 0.0325);Gain of ubiquitination at E359 (P = 0.0325);
MVP		0.84
MPC		0.33
ClinPred		0.93	D
GERP RS		4.7
Varity_R		0.27
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs876657702; hg19: chr11-47367773;