11-47350502-C-G

Position:

chr11-47350502-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000256.3(MYBPC3):c.406G>C(p.Gly136Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,405,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.15

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 4 ACMG points.

PM1

In a region_of_interest Disordered (size 46) in uniprot entity MYPC3_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000256.3

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.406G>C	p.Gly136Arg	missense_variant, splice_region_variant	3/35	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.406G>C	p.Gly136Arg	missense_variant, splice_region_variant	3/35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.406G>C	p.Gly136Arg	missense_variant, splice_region_variant	3/34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 linkuse as main transcript	n.406G>C		splice_region_variant, non_coding_transcript_exon_variant	3/27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000596

AC:

AN:

167850

Hom.:

AF XY:

0.0000110

AC XY:

AN XY:

91048

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000879

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1405936

Hom.:

Cov.:

AF XY:

0.00000287

AC XY:

AN XY:

695702

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000297

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000271

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This missense variant replaces glycine with arginine at codon 136 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 1/167850 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2023	This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 136 of the MYBPC3 protein (p.Gly136Arg). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

CardioboostCm

Benign

0.0033

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.082

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.59

N;N;N

REVEL

Benign

0.092

Sift

Benign

0.24

T;T;T

Sift4G

Benign

0.45

T;T;T

Polyphen

0.090

B;.;.

Vest4

0.28

MutPred

0.27

Loss of catalytic residue at P132 (P = 0.0722);Loss of catalytic residue at P132 (P = 0.0722);Loss of catalytic residue at P132 (P = 0.0722);

MVP

0.78

MPC

0.26

ClinPred

0.17

GERP RS

3.6

Varity_R

0.082

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.48

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.48

Position offset: 0

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