chr12-101651253-A-T

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.1386A>T(p.Thr462Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0578 in 1,613,834 control chromosomes in the GnomAD database, including 3,420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.086 ( 822 hom., cov: 32)

Exomes 𝑓: 0.055 ( 2598 hom. )

Consequence

MYBPC1
NM_002465.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.340

Publications

7 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 12-101651253-A-T is Benign according to our data. Variant chr12-101651253-A-T is described in ClinVar as Benign. ClinVar VariationId is 129641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.34 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC1	NM_002465.4 link	c.1386A>T	p.Thr462Thr	synonymous_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.1386A>T	p.Thr462Thr	synonymous_variant	Exon 16 of 32	1	NM_002465.4	ENSP00000354849.2		Q00872-4
MYBPC1	ENST00000551300.5 link	c.1014A>T	p.Thr338Thr	synonymous_variant	Exon 17 of 32	1		ENSP00000447116.1		G3V1V7

Frequencies

GnomAD3 genomes

AF:

0.0861

AC:

13081

AN:

151972

Hom.:

823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.180

Gnomad AMI

AF:

0.186

Gnomad AMR

AF:

0.0495

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.00404

Gnomad SAS

AF:

0.0477

Gnomad FIN

AF:

0.0461

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0547

Gnomad OTH

AF:

0.0758

GnomAD2 exomes

AF:

0.0541

AC:

13616

AN:

251460

AF XY:

0.0529

show subpopulations

Gnomad AFR exome

AF:

0.178

Gnomad AMR exome

AF:

0.0330

Gnomad ASJ exome

AF:

0.0267

Gnomad EAS exome

AF:

0.00484

Gnomad FIN exome

AF:

0.0445

Gnomad NFE exome

AF:

0.0570

Gnomad OTH exome

AF:

0.0534

GnomAD4 exome

AF:

0.0548

AC:

80128

AN:

1461744

Hom.:

2598

Cov.:

AF XY:

0.0545

AC XY:

39600

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.178

AC:

5971

AN:

33470

American (AMR)

AF:

0.0354

AC:

1583

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

760

AN:

26132

East Asian (EAS)

AF:

0.00264

AC:

105

AN:

39698

South Asian (SAS)

AF:

0.0475

AC:

4095

AN:

86256

European-Finnish (FIN)

AF:

0.0471

AC:

2518

AN:

53418

Middle Eastern (MID)

AF:

0.0439

AC:

253

AN:

5768

European-Non Finnish (NFE)

AF:

0.0554

AC:

61634

AN:

1111892

Other (OTH)

AF:

0.0531

AC:

3209

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

4361

8722

13083

17444

21805

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2332

4664

6996

9328

11660

<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:

0.0861

AC:

13093

AN:

152090

Hom.:

822

Cov.:

AF XY:

0.0833

AC XY:

6194

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.180

AC:

7443

AN:

41460

American (AMR)

AF:

0.0494

AC:

754

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0291

AC:

101

AN:

3472

East Asian (EAS)

AF:

0.00405

AC:

AN:

5180

South Asian (SAS)

AF:

0.0477

AC:

230

AN:

4820

European-Finnish (FIN)

AF:

0.0461

AC:

487

AN:

10570

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0548

AC:

3724

AN:

68006

Other (OTH)

AF:

0.0750

AC:

158

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

570

1141

1711

2282

2852

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<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:

0.0582

Hom.:

120

Bravo

AF:

0.0895

Asia WGS

AF:

0.0330

AC:

113

AN:

3478

EpiCase

AF:

0.0516

EpiControl

AF:

0.0535

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

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

- -

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

- -

not provided

Benign:2

Jul 31, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Arthrogryposis, distal, type 1B

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

3.2

(source)

DANN

Benign

0.71

PhyloP100

0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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