rs876657871

Positions:

• chr11-47333960-T-C

Variant summary

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

The NM_000256.3(MYBPC3):​c.2956A>G​(p.Lys986Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,432,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.54

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2956A>G	p.Lys986Glu	missense_variant	28/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2956A>G	p.Lys986Glu	missense_variant	28/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2956A>G	p.Lys986Glu	missense_variant	27/34	5		ENSP00000382193	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000492 AC: 1 AN: 203302 Hom.: 0 AF XY: 0.00000911 AC XY: 1 AN XY: 109746

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: 0.0000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000161 AC: 23 AN: 1432802 Hom.: 0 Cov.: 33 AF XY: 0.0000155 AC XY: 11 AN XY: 710014

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: 0.0000209

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000469 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 12, 2015

The p.Lys986Glu variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy. Data from large population studies are insufficient to de termine its frequency. Lysine (Lys) at position 986 is not conserved in mammals or evolutionarily distant species and the change to glutamic acid (Glu) was pre dicted to be benign using a computational tool clinically validated by our labor atory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, the clinical significance of the p.Lys986Glu variant is uncertain. -

Dilated cardiomyopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Oct 10, 2019

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

The p.K986E variant (also known as c.2956A>G), located in coding exon 28 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 2956. The lysine at codon 986 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Harper AR et al. Nat Genet, 2021 Feb;53:135-142). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
CardioboostCm	Benign	0.0088
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.6	D;.;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.015	D;.;D
Sift4G	Uncertain	0.010	D;D;D
Vest4		0.56
MVP		0.86
MPC		0.45
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.54
gMVP		0.83

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: rs876657871; hg19: chr11-47355511;