rs193922382

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000256.3(MYBPC3):c.2914C>T(p.Arg972Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000176 in 1,576,500 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R972Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 3.78

Publications

5 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011862069).

BP6

Variant 11-47334002-G-A is Benign according to our data. Variant chr11-47334002-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.2914C>T	p.Arg972Trp	missense_variant	Exon 28 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 link	c.2914C>T	p.Arg972Trp	missense_variant	Exon 28 of 35	5	NM_000256.3	ENSP00000442795.1		Q14896-1
MYBPC3	ENST00000399249.6 link	c.2914C>T	p.Arg972Trp	missense_variant	Exon 27 of 34	5		ENSP00000382193.2		A8MXZ9

Frequencies

GnomAD3 genomes

AF:

0.000867

AC:

132

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000478

GnomAD2 exomes

AF:

0.000226

AC:

AN:

185800

AF XY:

0.000219

show subpopulations

Gnomad AFR exome

AF:

0.00371

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

144

AN:

1424154

Hom.:

Cov.:

AF XY:

0.0000752

AC XY:

AN XY:

705094

show subpopulations

African (AFR)

AF:

0.00318

AC:

104

AN:

32670

American (AMR)

AF:

0.0000766

AC:

AN:

39160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25502

East Asian (EAS)

AF:

0.00

AC:

AN:

37546

South Asian (SAS)

AF:

0.00

AC:

AN:

81024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.0000284

AC:

AN:

1093396

Other (OTH)

AF:

0.000102

AC:

AN:

58920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000873

AC:

133

AN:

152346

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00298

AC:

124

AN:

41578

American (AMR)

AF:

0.000457

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.000448

Hom.:

Bravo

AF:

0.000960

ESP6500AA

AF:

0.00290

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000185

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 29, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22958901) -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Oct 02, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MYBPC3 c.2914C>T (p.Arg972Trp) results in a non-conservative amino acid change located in the Immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 185800 control chromosomes, predominantly at a frequency of 0.0037 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.7-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2914C>T has been reported in the literature in individuals affected with Cardiomyopathy without strong evidence of causality (Bick_2012, Burstein_2021). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22958901, 32746448). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 03, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 23, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg972Trp variant in MYBPC3 is classified as benign because it has been identified in 0.3% (58/18682) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). In addition, one mammalian species (elephant) carries a tryptophan at this position, despite high nearby amino acid conservation, further supporting a benign role. ACMG/AMP Criteria applied: BA1. -

Cardiomyopathy

Benign:2

Nov 30, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 10, 2022

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Aug 02, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

0.25

CardioboostCm

Benign

0.021

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;T;T

Eigen

Benign

-0.0024

Eigen_PC

Benign

0.089

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.1

M;.;.

PhyloP100

3.8

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.5

D;.;D

REVEL

Benign

0.11

Sift

Uncertain

0.021

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.26

MVP

0.72

MPC

0.23

ClinPred

0.078

GERP RS

3.1

Varity_R

0.21

gMVP

0.66

Mutation Taster

=79/21

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over