11-47351347-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000256.3(MYBPC3):c.184A>C(p.Thr62Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000234 in 1,601,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T62A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:7

Conservation

PhyloP100: 3.84

Publications

4 publications found

Variant links:

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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
left ventricular noncompaction 10
Inheritance: AD, AR 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
congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy
Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17208287).

BP6

Variant 11-47351347-T-G is Benign according to our data. Variant chr11-47351347-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42577.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.184A>C	p.Thr62Pro	missense	Exon 2 of 35	NP_000247.2	Q14896-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.184A>C	p.Thr62Pro	missense	Exon 2 of 35	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6	TSL:5	c.184A>C	p.Thr62Pro	missense	Exon 2 of 34	ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1	TSL:5	n.184A>C		non_coding_transcript_exon	Exon 2 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.000382

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000127

AC:

AN:

228228

AF XY:

0.000137

show subpopulations

Gnomad AFR exome

AF:

0.0000750

Gnomad AMR exome

AF:

0.0000306

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000263

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000236

AC:

342

AN:

1449466

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

167

AN XY:

719936

show subpopulations

African (AFR)

AF:

0.0000604

AC:

AN:

33122

American (AMR)

AF:

0.00

AC:

AN:

43262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25812

East Asian (EAS)

AF:

0.00

AC:

AN:

38896

South Asian (SAS)

AF:

0.00

AC:

AN:

84134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000295

AC:

326

AN:

1106576

Other (OTH)

AF:

0.000234

AC:

AN:

59942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000217

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41478

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000229

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000350

AC:

ExAC

AF:

0.000116

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (3)

Cardiomyopathy (2)

Hypertrophic cardiomyopathy (2)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy 4 (1)

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (1)

Left ventricular noncompaction 10 (1)

Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

CardioboostCm

Benign

0.0030

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.18

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.74

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.66

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

PhyloP100

3.8

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.33

Sift

Benign

0.10

Sift4G

Benign

0.10

Polyphen

0.30

Vest4

0.73

MVP

0.82

MPC

0.37

ClinPred

0.061

GERP RS

0.40

Varity_R

0.77

gMVP

0.64

Mutation Taster

=7/93

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over