12-101595081-C-T

Position:

chr12-101595081-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS1_Supporting

The NM_002465.4(MYBPC1):c.11C>T(p.Pro4Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,612,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MYBPC1
NM_002465.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.37

Variant links:

Genes affected

MYBPC1 (HGNC:7549): (myosin binding protein C1) This gene encodes a member of the myosin-binding protein C family. Myosin-binding protein C family members are myosin-associated proteins found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. The encoded protein is the slow skeletal muscle isoform of myosin-binding protein C and plays an important role in muscle contraction by recruiting muscle-type creatine kinase to myosin filaments. Mutations in this gene are associated with distal arthrogryposis type I. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

MYBPC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29619545).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000205 (30/1460816) while in subpopulation NFE AF= 0.000027 (30/1111120). AF 95% confidence interval is 0.0000192. There are 0 homozygotes in gnomad4_exome. There are 15 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC1	NM_002465.4 link	c.11C>T	p.Pro4Leu	missense_variant	1/32	ENST00000361466.7	NP_002456.2	Q00872-4Q86TA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC1	ENST00000361466.7 link	c.11C>T	p.Pro4Leu	missense_variant	1/32	1	NM_002465.4	ENSP00000354849.2		Q00872-4
MYBPC1	ENST00000551300 link	c.-458C>T		5_prime_UTR_variant	1/32	1		ENSP00000447116.1		G3V1V7

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151658

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251132

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1460816

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726764

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151658

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74076

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2024

The c.11C>T (p.P4L) alteration is located in exon 1 (coding exon 1) of the MYBPC1 gene. This alteration results from a C to T substitution at nucleotide position 11, causing the proline (P) at amino acid position 4 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

.;.;.;.;.;T;.;.;.;.;.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.83

T;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.30

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

0.34

N;N;N;.;N;.;N;N;N;N;N;N

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-4.0

D;D;D;D;N;D;D;D;D;D;N;D

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 0.18

.;.;.;.;D;B;D;.;.;.;.;D

Vest4

0.34

MutPred

0.27

Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);

MVP

0.71

MPC

0.066

ClinPred

0.97

GERP RS

5.9

Varity_R

0.33

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over