11-47333924-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_000256.3(MYBPC3):c.2992C>G(p.Gln998Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,571,272 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q998P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0026 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 48 hom. )

Consequence

MYBPC3
NM_000256.3 missense, splice_region

Scores

Splicing: ADA: 0.6273

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: 9.54

Publications

28 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 -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47333923-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1449122.

BP4

Computational evidence support a benign effect (MetaRNN=0.011652589).

BP6

Variant 11-47333924-G-C is Benign according to our data. Variant chr11-47333924-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00263 (401/152368) while in subpopulation AMR AF = 0.0197 (302/15302). AF 95% confidence interval is 0.0179. There are 7 homozygotes in GnomAd4. There are 220 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.2992C>G	p.Gln998Glu	missense_variant, splice_region_variant	Exon 28 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 link	c.2992C>G	p.Gln998Glu	missense_variant, splice_region_variant	Exon 28 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6 link	c.2992C>G	p.Gln998Glu	missense_variant, splice_region_variant	Exon 27 of 34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

403

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0198

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0140

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00708

AC:

1305

AN:

184304

AF XY:

0.00564

show subpopulations

Gnomad AFR exome

AF:

0.000289

Gnomad AMR exome

AF:

0.0387

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0160

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000770

Gnomad OTH exome

AF:

0.00491

GnomAD4 exome

AF:

0.00149

AC:

2109

AN:

1418904

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

947

AN XY:

701862

show subpopulations

African (AFR)

AF:

0.000247

AC:

AN:

32426

American (AMR)

AF:

0.0381

AC:

1446

AN:

37972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25398

East Asian (EAS)

AF:

0.0125

AC:

464

AN:

37226

South Asian (SAS)

AF:

0.000496

AC:

AN:

80658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50488

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

1090238

Other (OTH)

AF:

0.00185

AC:

109

AN:

58826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

121

242

362

483

604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00263

AC:

401

AN:

152368

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

220

AN XY:

74522

show subpopulations

African (AFR)

AF:

0.000264

AC:

AN:

41592

American (AMR)

AF:

0.0197

AC:

302

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0139

AC:

AN:

5188

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

102

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:

0.000964

Hom.:

Bravo

AF:

0.00511

ExAC

AF:

0.00347

AC:

416

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Mar 16, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:provider interpretation

reclassified to likely benign based on 2015 re-review. Data from that re-review is summarized in DOI: 10.1161/CIRCGENETICS.116.001700.

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 01, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYBPC3: PM5, BP4, BS1, BS2

Dec 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28498465, 22763267, 15519027, 27650965, 26332594, 31918855)

Jun 06, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:5

Jul 10, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gln998Glu in exon 28 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 9% (90/1000) of Latino chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs11570112).

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 30, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypertrophic cardiomyopathy 4

Benign:4

May 19, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 31, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 29, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Left ventricular noncompaction 10

Benign:1

Jan 29, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Cardiomyopathy

Benign:1

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Benign:1

Apr 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Primary dilated cardiomyopathy;C0878544:Cardiomyopathy

Benign:1

Jun 11, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Primary dilated cardiomyopathy

Benign:1

May 27, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Hypertrophic cardiomyopathy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Primary familial hypertrophic cardiomyopathy

Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Cardiovascular phenotype

Benign:1

Sep 29, 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

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

D;T;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.67

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.9

L;.;.

PhyloP100

9.5

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.6

D;.;D

Sift

Uncertain

0.0040

D;.;D

Sift4G

Uncertain

0.0050

D;D;D

Vest4

0.90

ClinPred

0.056

GERP RS

4.1

Varity_R

0.46

gMVP

0.68

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.63

dbscSNV1_RF

Benign

0.44

Splicevardb

2.0

SpliceAI score (max)

0.11

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