11-47351337-G-T

Variant names:

• chr11-47351337-G-T
• rs753300898
• NM_000256.3:c.194C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000256.3(MYBPC3):​c.194C>A​(p.Thr65Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T65M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.34
• Publications: 8 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.194C>A	p.Thr65Lys	missense_variant	Exon 2 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.194C>A	p.Thr65Lys	missense_variant	Exon 2 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.194C>A	p.Thr65Lys	missense_variant	Exon 2 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.194C>A		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445126 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 717344

African (AFR) AF: 0.00 AC: 0 AN: 32988

American (AMR) AF: 0.00 AC: 0 AN: 42572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25734

East Asian (EAS) AF: 0.00 AC: 0 AN: 38626

South Asian (SAS) AF: 0.00 AC: 0 AN: 83562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104416

Other (OTH) AF: 0.00 AC: 0 AN: 59780

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74382

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
CardioboostCm	Benign	0.010
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.9	L;.;.
PhyloP100		6.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.076	T;T;T
Polyphen		0.97	D;.;.
Vest4		0.45
MutPred		0.65		Gain of ubiquitination at T65 (P = 0.0085);Gain of ubiquitination at T65 (P = 0.0085);Gain of ubiquitination at T65 (P = 0.0085);
MVP		0.90
MPC		0.56
ClinPred		0.92	D
GERP RS		3.4
Varity_R		0.61
gMVP		0.61
Mutation Taster		=51/49	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: rs753300898; hg19: chr11-47372888;