dbSNP rs25667: MYBPC2:p.Arg1089His (chr19-50464383-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004533.4(MYBPC2):c.3266G>A(p.Arg1089His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,609,318 control chromosomes in the GnomAD database, including 30,503 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 2310 hom., cov: 32)

Exomes 𝑓: 0.19 ( 28193 hom. )

Consequence

MYBPC2
NM_004533.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.547

Publications

23 publications found

Variant links:

Genes affected

MYBPC2 (HGNC:7550): (myosin binding protein C2) This gene encodes a member of the myosin-binding protein C family. This family includes the fast-, slow- and cardiac-type isoforms, each of which is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. The protein encoded by this locus is referred to as the fast-type isoform. Mutations in the related but distinct genes encoding the slow-type and cardiac-type isoforms have been associated with distal arthrogryposis, type 1 and hypertrophic cardiomyopathy, respectively. [provided by RefSeq, Jul 2012]

MYBPC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031134486).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC2	NM_004533.4 link	c.3266G>A	p.Arg1089His	missense_variant	Exon 27 of 28	ENST00000357701.6	NP_004524.3	Q14324A0A140VJQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC2	ENST00000357701.6 link	c.3266G>A	p.Arg1089His	missense_variant	Exon 27 of 28	1	NM_004533.4	ENSP00000350332.4		Q14324
MYBPC2	ENST00000597498.1 link	n.153G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23729

AN:

152036

Hom.:

2310

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0412

Gnomad AMI

AF:

0.190

Gnomad AMR

AF:

0.256

Gnomad ASJ

AF:

0.193

Gnomad EAS

AF:

0.121

Gnomad SAS

AF:

0.168

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.193

Gnomad OTH

AF:

0.187

GnomAD2 exomes

AF:

0.199

AC:

48153

AN:

242206

AF XY:

0.196

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.329

Gnomad ASJ exome

AF:

0.195

Gnomad EAS exome

AF:

0.107

Gnomad FIN exome

AF:

0.205

Gnomad NFE exome

AF:

0.202

Gnomad OTH exome

AF:

0.215

GnomAD4 exome

AF:

0.193

AC:

280679

AN:

1457164

Hom.:

28193

Cov.:

AF XY:

0.191

AC XY:

138654

AN XY:

724352

show subpopulations

African (AFR)

AF:

0.0356

AC:

1190

AN:

33430

American (AMR)

AF:

0.316

AC:

13871

AN:

43942

Ashkenazi Jewish (ASJ)

AF:

0.193

AC:

5021

AN:

25952

East Asian (EAS)

AF:

0.136

AC:

5407

AN:

39618

South Asian (SAS)

AF:

0.168

AC:

14282

AN:

85198

European-Finnish (FIN)

AF:

0.206

AC:

10958

AN:

53142

Middle Eastern (MID)

AF:

0.296

AC:

1705

AN:

5762

European-Non Finnish (NFE)

AF:

0.195

AC:

216870

AN:

1109884

Other (OTH)

AF:

0.189

AC:

11375

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

11575

23150

34725

46300

57875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7520

15040

22560

30080

37600

<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:

0.156

AC:

23728

AN:

152154

Hom.:

2310

Cov.:

AF XY:

0.159

AC XY:

11827

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0410

AC:

1703

AN:

41542

American (AMR)

AF:

0.256

AC:

3908

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.193

AC:

670

AN:

3468

East Asian (EAS)

AF:

0.121

AC:

628

AN:

5176

South Asian (SAS)

AF:

0.168

AC:

811

AN:

4820

European-Finnish (FIN)

AF:

0.209

AC:

2207

AN:

10582

Middle Eastern (MID)

AF:

0.327

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.193

AC:

13140

AN:

67986

Other (OTH)

AF:

0.186

AC:

392

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

992

1984

2977

3969

4961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

248

496

744

992

1240

<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:

0.181

Hom.:

5849

Bravo

AF:

0.157

TwinsUK

AF:

0.206

AC:

764

ALSPAC

AF:

0.206

AC:

792

ESP6500AA

AF:

0.0406

AC:

171

ESP6500EA

AF:

0.191

AC:

1622

ExAC

AF:

0.193

AC:

23389

Asia WGS

AF:

0.158

AC:

552

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0018

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

-0.55

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.69

REVEL

Benign

0.056

Sift

Benign

0.56

Sift4G

Benign

0.24

Polyphen

0.0020

Vest4

0.058

MPC

0.18

ClinPred

0.00079

GERP RS

-0.52

Varity_R

0.053

gMVP

0.44

Mutation Taster

=97/3

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over