rs730880572

Variant names:

• chr11-47337431-C-A
• NM_000256.3:c.2562G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-47337431-C-A
• chr11-47337431-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000256.3(MYBPC3):​c.2562G>T​(p.Met854Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M854L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48

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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22665963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2562G>T	p.Met854Ile	missense_variant	Exon 25 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2562G>T	p.Met854Ile	missense_variant	Exon 25 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2562G>T	p.Met854Ile	missense_variant	Exon 24 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.*67G>T		non_coding_transcript_exon_variant	Exon 25 of 27	5		ENSP00000444259.1
MYBPC3	ENST00000544791.1	n.*67G>T		3_prime_UTR_variant	Exon 25 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457144 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 724490

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: 9.01e-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	Pathogenic	0.60
CardioboostCm	Benign	0.0088
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.066	T;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.45	N;.;N
REVEL	Benign	0.22
Sift	Benign	0.75	T;.;T
Sift4G	Benign	0.54	T;T;T
Vest4		0.47
MVP		0.73
MPC		0.41
ClinPred		0.43	T
GERP RS		4.6
Varity_R		0.25
gMVP		0.42

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: chr11-47358982;