NM_000256.3:c.649A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000256.3(MYBPC3):c.649A>G(p.Ser217Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00109 in 1,605,074 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S217N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 19 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:13

Conservation

PhyloP100: 4.16

Publications

22 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
left ventricular noncompaction 10
Inheritance: AD, AR 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
congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy
Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 21 uncertain in NM_000256.3

BP4

Computational evidence support a benign effect (MetaRNN=0.009872884).

BP6

Variant 11-47349779-T-C is Benign according to our data. Variant chr11-47349779-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42780.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0011 (167/152378) while in subpopulation SAS AF = 0.0106 (51/4832). AF 95% confidence interval is 0.00825. There are 3 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.649A>G	p.Ser217Gly	missense	Exon 5 of 35	NP_000247.2	Q14896-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.649A>G	p.Ser217Gly	missense	Exon 5 of 35	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6	TSL:5	c.649A>G	p.Ser217Gly	missense	Exon 5 of 34	ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1	TSL:5	n.649A>G		non_coding_transcript_exon	Exon 5 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

168

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0105

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00186

AC:

447

AN:

240264

AF XY:

0.00245

show subpopulations

Gnomad AFR exome

AF:

0.000133

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.000202

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000193

Gnomad NFE exome

AF:

0.000907

Gnomad OTH exome

AF:

0.00151

GnomAD4 exome

AF:

0.00109

AC:

1588

AN:

1452696

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1045

AN XY:

722992

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33458

American (AMR)

AF:

0.000202

AC:

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0107

AC:

919

AN:

85930

European-Finnish (FIN)

AF:

0.000286

AC:

AN:

45444

Middle Eastern (MID)

AF:

0.00801

AC:

AN:

5620

European-Non Finnish (NFE)

AF:

0.000485

AC:

539

AN:

1111606

Other (OTH)

AF:

0.000962

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

196

295

393

491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

AF:

0.00110

AC:

167

AN:

152378

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.000264

AC:

AN:

41594

American (AMR)

AF:

0.00124

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0106

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00112

AC:

AN:

68034

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.000786

ESP6500AA

AF:

0.000482

AC:

ESP6500EA

AF:

0.00119

AC:

ExAC

AF:

0.00209

AC:

253

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00142

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hypertrophic cardiomyopathy (3)

not specified (3)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy 4 (1)

Left ventricular noncompaction 10 (1)

Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.36

Eigen

Benign

0.018

Eigen_PC

Benign

-0.017

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0099

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.8

PhyloP100

4.2

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.32

Sift

Uncertain

0.0040

Sift4G

Benign

0.066

Polyphen

0.91

Vest4

0.28

MVP

0.86

MPC

0.20

ClinPred

0.064

GERP RS

3.7

Varity_R

0.32

gMVP

0.67

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over