chr11-47335077-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000256.3(MYBPC3):c.2870C>G(p.Thr957Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,595,244 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00087 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 4 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:12

Conservation

PhyloP100: 1.07

Publications

15 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02241832).

BP6

Variant 11-47335077-G-C is Benign according to our data. Variant chr11-47335077-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36607.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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.2870C>G	p.Thr957Ser	missense	Exon 27 of 35	NP_000247.2	Q14896-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.2870C>G	p.Thr957Ser	missense	Exon 27 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.2870C>G	p.Thr957Ser	missense	Exon 26 of 34	ENSP00000382193.2	A8MXZ9

Frequencies

GnomAD3 genomes

AF:

0.000867

AC:

132

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00146

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00101

AC:

237

AN:

235526

AF XY:

0.00110

show subpopulations

Gnomad AFR exome

AF:

0.000205

Gnomad AMR exome

AF:

0.000649

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000238

Gnomad NFE exome

AF:

0.00166

Gnomad OTH exome

AF:

0.000354

GnomAD4 exome

AF:

0.00170

AC:

2459

AN:

1442890

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

1150

AN XY:

716100

show subpopulations

African (AFR)

AF:

0.000336

AC:

AN:

32756

American (AMR)

AF:

0.000627

AC:

AN:

43076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25484

East Asian (EAS)

AF:

0.00

AC:

AN:

38756

South Asian (SAS)

AF:

0.000836

AC:

AN:

83770

European-Finnish (FIN)

AF:

0.000416

AC:

AN:

52858

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00202

AC:

2228

AN:

1100974

Other (OTH)

AF:

0.00170

AC:

101

AN:

59510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

139

278

417

556

695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.000866

AC:

132

AN:

152354

Hom.:

Cov.:

AF XY:

0.000832

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41586

American (AMR)

AF:

0.000522

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000827

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00146

AC:

AN:

68026

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00148

Hom.:

Bravo

AF:

0.000865

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00133

AC:

ExAC

AF:

0.000993

AC:

120

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Cardiomyopathy (2)

Hypertrophic cardiomyopathy 4 (2)

Primary familial hypertrophic cardiomyopathy (2)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy (1)

Left ventricular noncompaction 10 (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

CardioboostCm

Benign

0.00078

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.38

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.42

M_CAP

Benign

0.064

MetaRNN

Benign

0.022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

1.1

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.29

Sift

Benign

0.35

Sift4G

Benign

0.20

Vest4

0.67

MVP

0.75

MPC

0.20

ClinPred

0.024

GERP RS

0.79

Varity_R

0.13

gMVP

0.28

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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