rs3729953

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000256.3(MYBPC3):c.2547C>T(p.Val849Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,612,412 control chromosomes in the GnomAD database, including 1,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 121 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1518 hom. )

Consequence

MYBPC3
NM_000256.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 1.32

Publications

11 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: 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

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 11-47337446-G-A is Benign according to our data. Variant chr11-47337446-G-A is described in ClinVar as Benign. ClinVar VariationId is 42638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.2547C>T	p.Val849Val	synonymous_variant	Exon 25 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYBPC3	ENST00000545968.6 link	c.2547C>T	p.Val849Val	synonymous_variant	Exon 25 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6 link	c.2547C>T	p.Val849Val	synonymous_variant	Exon 24 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1 link	n.*52C>T		non_coding_transcript_exon_variant	Exon 25 of 27	5		ENSP00000444259.1
MYBPC3	ENST00000544791.1 link	n.*52C>T		3_prime_UTR_variant	Exon 25 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes

AF:

0.0333

AC:

5071

AN:

152214

Hom.:

123

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0208

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.0434

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.0465

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0372

Gnomad OTH

AF:

0.0325

GnomAD2 exomes

AF:

0.0435

AC:

10737

AN:

246988

AF XY:

0.0477

show subpopulations

Gnomad AFR exome

AF:

0.0218

Gnomad AMR exome

AF:

0.0132

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.0379

Gnomad FIN exome

AF:

0.0497

Gnomad NFE exome

AF:

0.0383

Gnomad OTH exome

AF:

0.0338

GnomAD4 exome

AF:

0.0396

AC:

57781

AN:

1460080

Hom.:

1518

Cov.:

AF XY:

0.0419

AC XY:

30440

AN XY:

726252

show subpopulations

African (AFR)

AF:

0.0219

AC:

734

AN:

33470

American (AMR)

AF:

0.0140

AC:

625

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0126

AC:

329

AN:

26116

East Asian (EAS)

AF:

0.0354

AC:

1403

AN:

39674

South Asian (SAS)

AF:

0.111

AC:

9545

AN:

86242

European-Finnish (FIN)

AF:

0.0498

AC:

2613

AN:

52454

Middle Eastern (MID)

AF:

0.0292

AC:

168

AN:

5758

European-Non Finnish (NFE)

AF:

0.0359

AC:

39870

AN:

1111324

Other (OTH)

AF:

0.0413

AC:

2494

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

3142

6285

9427

12570

15712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1476

2952

4428

5904

7380

<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:

0.0333

AC:

5069

AN:

152332

Hom.:

121

Cov.:

AF XY:

0.0351

AC XY:

2612

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0210

AC:

872

AN:

41592

American (AMR)

AF:

0.0159

AC:

243

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3472

East Asian (EAS)

AF:

0.0427

AC:

221

AN:

5174

South Asian (SAS)

AF:

0.116

AC:

560

AN:

4824

European-Finnish (FIN)

AF:

0.0465

AC:

493

AN:

10610

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0372

AC:

2533

AN:

68032

Other (OTH)

AF:

0.0326

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

264

527

791

1054

1318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0363

Hom.:

386

Bravo

AF:

0.0281

Asia WGS

AF:

0.116

AC:

404

AN:

3478

EpiCase

AF:

0.0360

EpiControl

AF:

0.0343

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 11, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 28, 2006

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy 4

Benign:4

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Left ventricular noncompaction 10

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiomyopathy

Benign:1

Mar 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 16, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

9.3

(source)

DANN

Benign

0.92

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over