rs764291

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002465.4(MYBPC1):c.2817A>G(p.Pro939Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,613,562 control chromosomes in the GnomAD database, including 57,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3755 hom., cov: 32)

Exomes 𝑓: 0.26 ( 53907 hom. )

Consequence

MYBPC1
NM_002465.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.05

Publications

19 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 12-101675299-A-G is Benign according to our data. Variant chr12-101675299-A-G is described in ClinVar as [Benign]. Clinvar id is 129645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC1	NM_002465.4 link	c.2817A>G	p.Pro939Pro	synonymous_variant	Exon 26 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.2817A>G	p.Pro939Pro	synonymous_variant	Exon 26 of 32	1	NM_002465.4	ENSP00000354849.2		Q00872-4
MYBPC1	ENST00000551300.5 link	c.2445A>G	p.Pro815Pro	synonymous_variant	Exon 27 of 32	1		ENSP00000447116.1		G3V1V7

Frequencies

GnomAD3 genomes

AF:

0.205

AC:

31184

AN:

152096

Hom.:

3757

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0767

Gnomad AMI

AF:

0.191

Gnomad AMR

AF:

0.182

Gnomad ASJ

AF:

0.304

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.266

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.279

Gnomad OTH

AF:

0.215

GnomAD2 exomes

AF:

0.223

AC:

55979

AN:

250936

AF XY:

0.231

show subpopulations

Gnomad AFR exome

AF:

0.0705

Gnomad AMR exome

AF:

0.137

Gnomad ASJ exome

AF:

0.302

Gnomad EAS exome

AF:

0.0861

Gnomad FIN exome

AF:

0.264

Gnomad NFE exome

AF:

0.276

Gnomad OTH exome

AF:

0.249

GnomAD4 exome

AF:

0.265

AC:

387138

AN:

1461346

Hom.:

53907

Cov.:

AF XY:

0.265

AC XY:

192720

AN XY:

726966

show subpopulations

African (AFR)

AF:

0.0727

AC:

2434

AN:

33470

American (AMR)

AF:

0.142

AC:

6350

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

7878

AN:

26128

East Asian (EAS)

AF:

0.0893

AC:

3544

AN:

39694

South Asian (SAS)

AF:

0.230

AC:

19822

AN:

86238

European-Finnish (FIN)

AF:

0.263

AC:

14062

AN:

53398

Middle Eastern (MID)

AF:

0.320

AC:

1842

AN:

5764

European-Non Finnish (NFE)

AF:

0.284

AC:

315685

AN:

1111608

Other (OTH)

AF:

0.257

AC:

15521

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

16460

32920

49379

65839

82299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.205

AC:

31177

AN:

152216

Hom.:

3755

Cov.:

AF XY:

0.203

AC XY:

15080

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0766

AC:

3185

AN:

41570

American (AMR)

AF:

0.182

AC:

2779

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

1053

AN:

3466

East Asian (EAS)

AF:

0.111

AC:

574

AN:

5186

South Asian (SAS)

AF:

0.225

AC:

1085

AN:

4824

European-Finnish (FIN)

AF:

0.266

AC:

2813

AN:

10580

Middle Eastern (MID)

AF:

0.344

AC:

101

AN:

294

European-Non Finnish (NFE)

AF:

0.279

AC:

18957

AN:

67974

Other (OTH)

AF:

0.216

AC:

456

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1226

2452

3679

4905

6131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.247

Hom.:

15096

Bravo

AF:

0.189

Asia WGS

AF:

0.152

AC:

531

AN:

3478

EpiCase

AF:

0.278

EpiControl

AF:

0.273

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

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Arthrogryposis, distal, type 1B

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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. -

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

BayesDel_noAF

Benign

-0.78

CADD

Benign

3.3

(source)

DANN

Benign

0.59

PhyloP100

-1.1

Mutation Taster

=100/0

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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rs764291

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