chr11-47349863-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000256.3(MYBPC3):c.565G>A(p.Val189Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,612,566 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. V189L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 20 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: 3.21

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain Ig-like C2-type 1 (size 103) in uniprot entity MYPC3_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000256.3

BP4

Computational evidence support a benign effect (MetaRNN=0.010700673).

BP6

Variant 11-47349863-C-T is Benign according to our data. Variant chr11-47349863-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47349863-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00257 (3755/1460190) while in subpopulation MID AF= 0.0128 (74/5762). AF 95% confidence interval is 0.0105. There are 20 homozygotes in gnomad4_exome. There are 1963 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.565G>A	p.Val189Ile	missense_variant	Exon 5 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 link	c.565G>A	p.Val189Ile	missense_variant	Exon 5 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.565G>A	p.Val189Ile	missense_variant	Exon 5 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.565G>A		non_coding_transcript_exon_variant	Exon 5 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

307

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000506

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00351

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00285

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00260

AC:

637

AN:

245140

Hom.:

AF XY:

0.00296

AC XY:

395

AN XY:

133466

show subpopulations

Gnomad AFR exome

AF:

0.000202

Gnomad AMR exome

AF:

0.00210

Gnomad ASJ exome

AF:

0.00414

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00397

Gnomad FIN exome

AF:

0.000430

Gnomad NFE exome

AF:

0.00334

Gnomad OTH exome

AF:

0.00353

GnomAD4 exome

AF:

0.00257

AC:

3755

AN:

1460190

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

1963

AN XY:

726326

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00227

Gnomad4 ASJ exome

AF:

0.00441

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00383

Gnomad4 FIN exome

AF:

0.000378

Gnomad4 NFE exome

AF:

0.00262

Gnomad4 OTH exome

AF:

0.00302

GnomAD4 genome

AF:

0.00201

AC:

307

AN:

152376

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00285

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00336

Hom.:

Bravo

AF:

0.00228

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000241

AC:

ESP6500EA

AF:

0.00345

AC:

ExAC

AF:

0.00256

AC:

310

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00431

EpiControl

AF:

0.00428

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Jun 20, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: provider interpretation

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22429680, 23861362, 24503780, 24721642, 25342278, 27483260, 21310275) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYBPC3: BS2 -

Oct 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 05, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val189Ile in exon 5 of MYBPC3: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (204/60142) of European chrom osomes, including 2 homozygotes, by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs11570052). -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 4

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 16, 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. -

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

- -

Cardiomyopathy

Benign:2

Feb 02, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy

Benign:2

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Left ventricular noncompaction 10

Benign:1

Feb 16, 2018

Illumina Laboratory Services, Illumina

Significance: 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Long QT syndrome

Benign:1

Nov 14, 2018

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy

Benign:1

May 26, 2015

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 05, 2019

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

0.20

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;T

Eigen

Benign

-0.022

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.052

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.1

L;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.42

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.40

T;T;T

Sift4G

Benign

0.57

T;T;T

Polyphen

0.20

B;.;.

Vest4

0.28

MVP

0.69

MPC

0.23

ClinPred

0.10

GERP RS

4.8

Varity_R

0.12

gMVP

0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over