12-101642527-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002465.4(MYBPC1):c.774C>T(p.Asp258Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,612,768 control chromosomes in the GnomAD database, including 71,493 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6643 hom., cov: 32)

Exomes 𝑓: 0.30 ( 64850 hom. )

Consequence

MYBPC1
NM_002465.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.819

Publications

17 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 12-101642527-C-T is Benign according to our data. Variant chr12-101642527-C-T is described in ClinVar as Benign. ClinVar VariationId is 129647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.819 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC1	NM_002465.4 link	c.774C>T	p.Asp258Asp	synonymous_variant	Exon 11 of 32	ENST00000361466.7	NP_002456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC1	ENST00000361466.7 link	c.774C>T	p.Asp258Asp	synonymous_variant	Exon 11 of 32	1	NM_002465.4	ENSP00000354849.2
MYBPC1	ENST00000551300.5 link	c.402C>T	p.Asp134Asp	synonymous_variant	Exon 12 of 32	1		ENSP00000447116.1

Frequencies

GnomAD3 genomes

AF:

0.292

AC:

44391

AN:

151958

Hom.:

6640

Cov.:

show subpopulations

Gnomad AFR

AF:

0.282

Gnomad AMI

AF:

0.246

Gnomad AMR

AF:

0.267

Gnomad ASJ

AF:

0.267

Gnomad EAS

AF:

0.395

Gnomad SAS

AF:

0.230

Gnomad FIN

AF:

0.338

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.292

GnomAD2 exomes

AF:

0.289

AC:

71831

AN:

248652

AF XY:

0.287

show subpopulations

Gnomad AFR exome

AF:

0.288

Gnomad AMR exome

AF:

0.239

Gnomad ASJ exome

AF:

0.269

Gnomad EAS exome

AF:

0.394

Gnomad FIN exome

AF:

0.333

Gnomad NFE exome

AF:

0.299

Gnomad OTH exome

AF:

0.295

GnomAD4 exome

AF:

0.296

AC:

432250

AN:

1460690

Hom.:

64850

Cov.:

AF XY:

0.294

AC XY:

213239

AN XY:

726522

show subpopulations

African (AFR)

AF:

0.280

AC:

9377

AN:

33476

American (AMR)

AF:

0.241

AC:

10724

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

6957

AN:

26098

East Asian (EAS)

AF:

0.390

AC:

15458

AN:

39664

South Asian (SAS)

AF:

0.222

AC:

19061

AN:

86006

European-Finnish (FIN)

AF:

0.333

AC:

17741

AN:

53348

Middle Eastern (MID)

AF:

0.312

AC:

1800

AN:

5766

European-Non Finnish (NFE)

AF:

0.300

AC:

333513

AN:

1111384

Other (OTH)

AF:

0.292

AC:

17619

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

17577

35155

52732

70310

87887

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11016

22032

33048

44064

55080

<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:

0.292

AC:

44408

AN:

152078

Hom.:

6643

Cov.:

AF XY:

0.293

AC XY:

21773

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.282

AC:

11697

AN:

41482

American (AMR)

AF:

0.266

AC:

4067

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

925

AN:

3470

East Asian (EAS)

AF:

0.396

AC:

2039

AN:

5154

South Asian (SAS)

AF:

0.231

AC:

1113

AN:

4820

European-Finnish (FIN)

AF:

0.338

AC:

3573

AN:

10566

Middle Eastern (MID)

AF:

0.371

AC:

109

AN:

294

European-Non Finnish (NFE)

AF:

0.295

AC:

20053

AN:

67986

Other (OTH)

AF:

0.289

AC:

608

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1624

3249

4873

6498

8122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.289

Hom.:

4125

Bravo

AF:

0.287

Asia WGS

AF:

0.290

AC:

1008

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

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

Nov 12, 2018

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: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

-0.36

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.82

Mutation Taster

=98/2

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over