Variant rs397515957 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000256.3(MYBPC3):c.2274C>T(p.Gly758=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 0.00200

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2274C>T	p.Gly758=	synonymous_variant	23/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.2274C>T	p.Gly758=	synonymous_variant	23/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2274C>T	p.Gly758=	synonymous_variant	22/34	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.2274C>T	p.Gly758=	synonymous_variant, NMD_transcript_variant	23/27	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249212

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135200

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain:3

Likely pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	May 08, 2019	MYBPC3 Gly758= has been previously reported in a HCM proband by another laboratory (LMM, ClinVar:SCV000059125) and is present at a low frequency in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a HCM proband, and other affected relatives (Bagnall et al., 2018). Splice prediction tool MaxEntScan predicts that this variant will result in aberrant splicing. RNA extracted from the blood of all 3 affected individuals showed that this causes a new splice donor and aberrant splicing of exon 23, resulting in a 36 base pair in-frame truncation (Bagnall et al., 2018). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant is rare in the general population (PM2), causes a truncated protein (PM4), segregates to affected family members (PP1) and in silico tools predict aberrant splicing to occur (PP3), therefore we classify MYBPC3 Gly758= as 'likely pathogenic'. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 05, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Studies have shown that this variant results in the activation of a cryptic splice site in exon 23 (PMID: 30025578). ClinVar contains an entry for this variant (Variation ID: 42609). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30025578). This variant is present in population databases (rs397515957, gnomAD no frequency). This sequence change affects codon 758 of the MYBPC3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 12 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 11, 2023	The p.Gly758Gly variant in MYBPC3 has been reported in at least 2 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 2 affected relatives from one family (Bagnall 2018 PMID: 30025578, LMM Data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42609) and has been identified in 0.0015% (1/68016) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools predict a splicing impact, resulting from the creation of a novel 5' (donor) splice site. This is corroborated by an vitro splicing study on patient RNA from blood, which showed aberrant splicing on exon 23 that resulted in a protein that is truncated by 12 amino acids and not expected to affect the reading frame (Bagnall 2018 PMID: 30025578). It is unclear how this truncation would cause disease. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM2_Supporting, PP3, PM4. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 27, 2023	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 13, 2023

RNA analysis revealed exon 23 was truncated by 36 nucleotides, leading to an in-frame deletion of 12 amino acids (Gly758-Ile769) (Bagnall et al., 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing.; Reported in ClinVar with conflicting classifications (ClinVar Variant ID# 42609; ClinVar); This variant is associated with the following publications: (PMID: 31243064, 30025578) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

Cadd

Benign

Dann

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.73

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.73

Position offset: 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