11-47348490-T-C

Position:

chr11-47348490-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000256.3(MYBPC3):c.706A>G(p.Ser236Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,612,892 control chromosomes in the GnomAD database, including 12,149 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.095 ( 786 hom., cov: 30)

Exomes 𝑓: 0.12 ( 11363 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.19

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=0.0027847886).

BP6

Variant 11-47348490-T-C is Benign according to our data. Variant chr11-47348490-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 42786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47348490-T-C is described in Lovd as [Benign]. Variant chr11-47348490-T-C is described in Lovd as [Likely_pathogenic]. Variant chr11-47348490-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.706A>G	p.Ser236Gly	missense_variant	6/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.706A>G	p.Ser236Gly	missense_variant	6/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.706A>G	p.Ser236Gly	missense_variant	6/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.706A>G	p.Ser236Gly	missense_variant, NMD_transcript_variant	6/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes

AF:

0.0947

AC:

14397

AN:

152056

Hom.:

784

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0535

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0746

Gnomad ASJ

AF:

0.107

Gnomad EAS

AF:

0.0276

Gnomad SAS

AF:

0.0617

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.128

Gnomad OTH

AF:

0.0889

GnomAD3 exomes

AF:

0.0964

AC:

23868

AN:

247526

Hom.:

1373

AF XY:

0.0978

AC XY:

13161

AN XY:

134536

show subpopulations

Gnomad AFR exome

AF:

0.0536

Gnomad AMR exome

AF:

0.0459

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.0291

Gnomad SAS exome

AF:

0.0682

Gnomad FIN exome

AF:

0.119

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.111

GnomAD4 exome

AF:

0.120

AC:

175560

AN:

1460718

Hom.:

11363

Cov.:

AF XY:

0.119

AC XY:

86305

AN XY:

726614

show subpopulations

Gnomad4 AFR exome

AF:

0.0521

Gnomad4 AMR exome

AF:

0.0487

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.0181

Gnomad4 SAS exome

AF:

0.0704

Gnomad4 FIN exome

AF:

0.127

Gnomad4 NFE exome

AF:

0.133

Gnomad4 OTH exome

AF:

0.111

GnomAD4 genome

AF:

0.0947

AC:

14417

AN:

152174

Hom.:

786

Cov.:

AF XY:

0.0923

AC XY:

6869

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0539

Gnomad4 AMR

AF:

0.0744

Gnomad4 ASJ

AF:

0.107

Gnomad4 EAS

AF:

0.0276

Gnomad4 SAS

AF:

0.0622

Gnomad4 FIN

AF:

0.121

Gnomad4 NFE

AF:

0.128

Gnomad4 OTH

AF:

0.0880

Alfa

AF:

0.117

Hom.:

2877

Bravo

AF:

0.0894

TwinsUK

AF:

0.135

AC:

501

ALSPAC

AF:

0.135

AC:

519

ESP6500AA

AF:

0.0574

AC:

239

ESP6500EA

AF:

0.126

AC:

1060

ExAC

AF:

0.100

AC:

12114

Asia WGS

AF:

0.0500

AC:

174

AN:

3478

EpiCase

AF:

0.125

EpiControl

AF:

0.129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 18, 2008	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hypertrophic cardiomyopathy 4

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -

Hypertrophic cardiomyopathy

Benign:4

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Left ventricular noncompaction 10

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 19, 2018

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

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

-0.61

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.22

DEOGEN2

Benign

0.15

T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.56

T;T;T

MetaRNN

Benign

0.0028

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.7

N;.;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.39

PROVEAN

Benign

2.2

N;N;N

REVEL

Benign

0.17

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.031

MPC

0.20

ClinPred

0.0085

GERP RS

5.1

Varity_R

0.15

gMVP

0.44

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