Genetic Variant MYBPC2:p.Pro26Ala (chr19-50435217-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004533.4(MYBPC2):c.76C>G(p.Pro26Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000847 in 1,180,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. P26S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.5e-7 ( 0 hom. )

Consequence

MYBPC2
NM_004533.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.365

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07016319).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004533.4. 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
	MYBPC2	NM_004533.4	MANE Select	c.76C>G	p.Pro26Ala	missense	Exon 2 of 28	NP_004524.3	A0A140VJQ0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYBPC2	ENST00000357701.6	TSL:1 MANE Select	c.76C>G	p.Pro26Ala	missense	Exon 2 of 28	ENSP00000350332.4	Q14324
MYBPC2	ENST00000966357.1		c.76C>G	p.Pro26Ala	missense	Exon 2 of 28	ENSP00000636416.1
MYBPC2	ENST00000966353.1		c.205C>G	p.Pro69Ala	missense	Exon 3 of 29	ENSP00000636412.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.47e-7

AC:

AN:

1180330

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

598222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28128

American (AMR)

AF:

0.00

AC:

AN:

41516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23962

East Asian (EAS)

AF:

0.00

AC:

AN:

37772

South Asian (SAS)

AF:

0.00

AC:

AN:

77942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51638

Middle Eastern (MID)

AF:

0.000189

AC:

AN:

5278

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

863182

Other (OTH)

AF:

0.00

AC:

AN:

50912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.775

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.52

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.0057

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.38

M_CAP

Benign

0.011

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.55

PhyloP100

-0.36

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.1

REVEL

Benign

0.045

Sift

Benign

0.076

Sift4G

Benign

0.13

Polyphen

0.0

Vest4

0.22

MutPred

0.29

Loss of catalytic residue at P26 (P = 0.0056)

MVP

0.19

MPC

0.13

ClinPred

0.085

GERP RS

-5.4

Varity_R

0.017

gMVP

0.043

Mutation Taster

=93/7

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over