rs1052373

Positions:

• chr11-47333236-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000256.3(MYBPC3):​c.3288G>A​(p.Glu1096Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,589,804 control chromosomes in the GnomAD database, including 104,276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12430 hom., cov: 32)
  • Exomes 𝑓: 0.35 (91846 hom.)
• Consequence: MYBPC3 NM_000256.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.00300

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 11-47333236-C-T is Benign according to our data. Variant chr11-47333236-C-T is described in ClinVar as [Benign]. Clinvar id is 42700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47333236-C-T is described in Lovd as [Benign]. Variant chr11-47333236-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.003 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3288G>A	p.Glu1096Glu	synonymous_variant	30/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3288G>A	p.Glu1096Glu	synonymous_variant	30/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3288G>A	p.Glu1096Glu	synonymous_variant	29/34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59338 AN: 151892 Hom.: 12433 Cov.: 32

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.401 AC: 84300 AN: 210138 Hom.: 18138 AF XY: 0.396 AC XY: 44833 AN XY: 113322

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.699

Gnomad SAS exome AF: 0.467

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.318

Gnomad OTH exome AF: 0.328

GnomAD4 exome AF: 0.348 AC: 500034 AN: 1437794 Hom.: 91846 Cov.: 56 AF XY: 0.349 AC XY: 248932 AN XY: 712858

Gnomad4 AFR exome AF: 0.494

Gnomad4 AMR exome AF: 0.425

Gnomad4 ASJ exome AF: 0.264

Gnomad4 EAS exome AF: 0.688

Gnomad4 SAS exome AF: 0.463

Gnomad4 FIN exome AF: 0.413

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.352

GnomAD4 genome AF: 0.390 AC: 59358 AN: 152010 Hom.: 12430 Cov.: 32 AF XY: 0.399 AC XY: 29637 AN XY: 74294

Gnomad4 AFR AF: 0.492

Gnomad4 AMR AF: 0.355

Gnomad4 ASJ AF: 0.268

Gnomad4 EAS AF: 0.686

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.429

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.334

Alfa AF: 0.316 Hom.: 18120

Bravo AF: 0.387

Asia WGS AF: 0.530 AC: 1841 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 20, 2008	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2012	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, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Aug 13, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 4 Benign:5

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Left ventricular noncompaction 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Oct 10, 2022	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.5
DANN	Benign	0.69

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

Other links and lift over

dbSNP: rs1052373; hg19: chr11-47354787; COSMIC: COSV57025052; COSMIC: COSV57025052;