chr12-101651385-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002465.4(MYBPC1):c.1518C>G(p.His506Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,664 control chromosomes in the GnomAD database, including 20,958 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1815 hom., cov: 32)

Exomes 𝑓: 0.16 ( 19143 hom. )

Consequence

MYBPC1
NM_002465.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.45

Publications

27 publications found

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 Gene-Disease associations (from GenCC):

arthrogryposis, distal, type 1B
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
myopathy, congenital, with tremor
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
lethal congenital contracture syndrome 4
Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
digitotalar dysmorphism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
lethal congenital contracture syndrome 3
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYBPC1 links:

ENSG00000257514 (HGNC:):

ENSG00000257514 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017406046).

BP6

Variant 12-101651385-C-G is Benign according to our data. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651385-C-G is described in CliVar as Benign. Clinvar id is 129642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC1	NM_002465.4 link	c.1518C>G	p.His506Gln	missense_variant	Exon 16 of 32	ENST00000361466.7	NP_002456.2	Q00872-4Q86TA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC1	ENST00000361466.7 link	c.1518C>G	p.His506Gln	missense_variant	Exon 16 of 32	1	NM_002465.4	ENSP00000354849.2		Q00872-4
MYBPC1	ENST00000551300.5 link	c.1146C>G	p.His382Gln	missense_variant	Exon 17 of 32	1		ENSP00000447116.1		G3V1V7

Frequencies

GnomAD3 genomes

AF:

0.148

AC:

22569

AN:

151980

Hom.:

1814

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.105

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.299

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.155

Gnomad OTH

AF:

0.155

GnomAD2 exomes

AF:

0.156

AC:

39160

AN:

251400

AF XY:

0.159

show subpopulations

Gnomad AFR exome

AF:

0.126

Gnomad AMR exome

AF:

0.0803

Gnomad ASJ exome

AF:

0.190

Gnomad EAS exome

AF:

0.293

Gnomad FIN exome

AF:

0.162

Gnomad NFE exome

AF:

0.157

Gnomad OTH exome

AF:

0.159

GnomAD4 exome

AF:

0.158

AC:

230827

AN:

1461566

Hom.:

19143

Cov.:

AF XY:

0.158

AC XY:

115165

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.119

AC:

3974

AN:

33468

American (AMR)

AF:

0.0836

AC:

3737

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.187

AC:

4899

AN:

26134

East Asian (EAS)

AF:

0.303

AC:

12040

AN:

39690

South Asian (SAS)

AF:

0.155

AC:

13343

AN:

86254

European-Finnish (FIN)

AF:

0.160

AC:

8520

AN:

53410

Middle Eastern (MID)

AF:

0.202

AC:

1165

AN:

5766

European-Non Finnish (NFE)

AF:

0.156

AC:

173435

AN:

1111742

Other (OTH)

AF:

0.161

AC:

9714

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

11281

22562

33842

45123

56404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6230

12460

18690

24920

31150

<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:

0.148

AC:

22562

AN:

152098

Hom.:

1815

Cov.:

AF XY:

0.149

AC XY:

11102

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.127

AC:

5248

AN:

41480

American (AMR)

AF:

0.105

AC:

1599

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.189

AC:

655

AN:

3472

East Asian (EAS)

AF:

0.299

AC:

1548

AN:

5172

South Asian (SAS)

AF:

0.160

AC:

769

AN:

4812

European-Finnish (FIN)

AF:

0.166

AC:

1757

AN:

10576

Middle Eastern (MID)

AF:

0.228

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.155

AC:

10510

AN:

67982

Other (OTH)

AF:

0.154

AC:

324

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

978

1956

2934

3912

4890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.149

Hom.:

1438

Bravo

AF:

0.144

TwinsUK

AF:

0.152

AC:

562

ALSPAC

AF:

0.154

AC:

593

ESP6500AA

AF:

0.130

AC:

571

ESP6500EA

AF:

0.148

AC:

1273

ExAC

AF:

0.157

AC:

19070

Asia WGS

AF:

0.204

AC:

708

AN:

3478

EpiCase

AF:

0.160

EpiControl

AF:

0.163

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Sep 04, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17000706, 23873045) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Arthrogryposis, distal, type 1B

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myopathy, congenital, with tremor

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lethal congenital contracture syndrome 4

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

.;.;.;.;.;T;.;.;.;.;.;.;D

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

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

MetaRNN

Benign

0.0017

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;L;.;.;.;.;L;L;.;.;.;.;L

PhyloP100

2.5

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.6

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

REVEL

Benign

0.27

Sift

Uncertain

0.012

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

.;.;.;.;D;D;D;.;.;.;.;.;D

Vest4

0.45

MutPred

0.67

.;.;.;.;.;Gain of catalytic residue at R497 (P = 0.0011);.;.;.;.;.;.;.;

MPC

0.76

ClinPred

0.039

GERP RS

3.6

Varity_R

0.58

gMVP

0.70

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over