Genetic Variant MYBPC3:p.Arg215Ser (chr11-47349785-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000256.3(MYBPC3):c.643C>A(p.Arg215Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.764

Publications

8 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: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 18 uncertain in NM_000256.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.643C>A	p.Arg215Ser	missense_variant	Exon 5 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYBPC3	ENST00000545968.6 link	c.643C>A	p.Arg215Ser	missense_variant	Exon 5 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6 link	c.643C>A	p.Arg215Ser	missense_variant	Exon 5 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1 link	n.643C>A		non_coding_transcript_exon_variant	Exon 5 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453760

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723420

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

85954

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111606

Other (OTH)

AF:

0.00

AC:

AN:

60306

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

CardioboostCm

Benign

0.011

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;T;T

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.69

T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.6

L;.;.

PhyloP100

0.76

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.4

D;D;D

REVEL

Uncertain

0.48

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.23

T;T;T

Vest4

0.90

ClinPred

0.94

GERP RS

2.8

Varity_R

0.49

gMVP

0.78

Mutation Taster

=11/89

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over