rs11570052

Positions:

chr11-47349863-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

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 -14 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].

BS2

High Homozygotes in GnomAdExome4 at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.565G>A	p.Val189Ile	missense_variant	5/35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.565G>A	p.Val189Ile	missense_variant	5/35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.565G>A	p.Val189Ile	missense_variant	5/34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 linkuse as main transcript	n.565G>A		non_coding_transcript_exon_variant	5/27	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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 22429680, 23861362, 24503780, 24721642, 25342278, 27483260, 21310275) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	- -
Likely benign, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 20, 2016	reclassified based on 2015 re-review. Data from that re-review is summarized in DOI: 10.1161/CIRCGENETICS.116.001700. -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MYBPC3: BS2 -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2015	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). -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 05, 2016	- -

Hypertrophic cardiomyopathy 4

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 16, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -

Hypertrophic cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	research	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	-	- -

Left ventricular noncompaction 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 16, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 14, 2018

- -

Primary familial hypertrophic cardiomyopathy

Benign:1

Benign, no assertion criteria provided

clinical testing

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

May 26, 2015

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2019

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