Genetic Variant MYBPC3:p.Ser13Arg (chr11-47351492-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000256.3(MYBPC3):c.39C>G(p.Ser13Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000697 in 1,434,940 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 Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. S13S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 4.42

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 4
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
left ventricular noncompaction 10
Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
atrial fibrillation
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MYBPC3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.39C>G	p.Ser13Arg	missense_variant	Exon 2 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 link	c.39C>G	p.Ser13Arg	missense_variant	Exon 2 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.39C>G	p.Ser13Arg	missense_variant	Exon 2 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.39C>G		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1434940

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708862

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33032

American (AMR)

AF:

0.00

AC:

AN:

43702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25382

East Asian (EAS)

AF:

0.00

AC:

AN:

38980

South Asian (SAS)

AF:

0.00

AC:

AN:

84494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093356

Other (OTH)

AF:

0.0000169

AC:

AN:

59112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Oct 06, 2014

Blueprint Genetics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

CardioboostCm

Benign

0.0095

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T;T

Eigen

Benign

-0.073

Eigen_PC

Benign

0.052

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.34

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.7

L;.;.

PhyloP100

4.4

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.056

Sift

Uncertain

0.0090

D;D;D

Sift4G

Uncertain

0.010

D;D;D

Polyphen

0.17

B;.;.

Vest4

0.35

MutPred

0.45

Loss of glycosylation at S13 (P = 0.022);Loss of glycosylation at S13 (P = 0.022);Loss of glycosylation at S13 (P = 0.022);

MVP

0.76

MPC

0.43

ClinPred

0.94

GERP RS

4.3

Varity_R

0.59

gMVP

0.35

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.46

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.46

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over