dbSNP rs199728019: MYBPC3:p.Gly596Arg (chr11-47341995-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000256.3(MYBPC3):c.1786G>C(p.Gly596Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,409,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.53

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.1786G>C	p.Gly596Arg	missense_variant	Exon 18 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.1786G>C	p.Gly596Arg	missense_variant	Exon 18 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.1786G>C	p.Gly596Arg	missense_variant	Exon 17 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.1786G>C		non_coding_transcript_exon_variant	Exon 18 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1409432

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

696172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32148

American (AMR)

AF:

0.00

AC:

AN:

36320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25318

East Asian (EAS)

AF:

0.00

AC:

AN:

36554

South Asian (SAS)

AF:

0.00

AC:

AN:

80210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1084182

Other (OTH)

AF:

0.0000171

AC:

AN:

58606

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

CardioboostCm

Uncertain

0.25

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

D;T;T

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.2

M;.;.

PhyloP100

7.5

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.5

D;.;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Vest4

0.89

MVP

0.95

MPC

0.90

ClinPred

1.0

GERP RS

5.1

Varity_R

0.75

gMVP

0.88

Mutation Taster

=27/73

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over