11-47335973-C-G

Variant names:

• chr11-47335973-C-G
• rs727504360
• NM_000256.3:c.2641G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000256.3(MYBPC3):​c.2641G>C​(p.Val881Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. V881F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.194
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39531034).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.2641G>C	p.Val881Leu	missense	Exon 26 of 35	NP_000247.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.2641G>C	p.Val881Leu	missense	Exon 26 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.2641G>C	p.Val881Leu	missense	Exon 25 of 34	ENSP00000382193.2
	MYBPC3	ENST00000544791.1	TSL:5	n.*146G>C		non_coding_transcript_exon	Exon 26 of 27	ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400348 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 692006

African (AFR) AF: 0.00 AC: 0 AN: 31038

American (AMR) AF: 0.00 AC: 0 AN: 37006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23488

East Asian (EAS) AF: 0.0000271 AC: 1 AN: 36872

South Asian (SAS) AF: 0.00 AC: 0 AN: 76496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4082

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082350

Other (OTH) AF: 0.00 AC: 0 AN: 57666

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
CardioboostCm	Uncertain	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		0.19
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.18
Sift	Benign	0.077	T
Sift4G	Uncertain	0.0070	D
Vest4		0.42
MVP		0.81
MPC		0.47
ClinPred		0.61	D
GERP RS		1.3
Varity_R		0.20
gMVP		0.45
Mutation Taster		=94/6	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: rs727504360; hg19: chr11-47357524;