12-101670340-T-C

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.2544T>C(p.Ile848Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.952 in 1,613,850 control chromosomes in the GnomAD database, including 731,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.95 ( 69053 hom., cov: 32)

Exomes 𝑓: 0.95 ( 662465 hom. )

Consequence

MYBPC1
NM_002465.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.458

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 12-101670340-T-C is Benign according to our data. Variant chr12-101670340-T-C is described in ClinVar as Benign. ClinVar VariationId is 129644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.458 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC1	NM_002465.4 link	c.2544T>C	p.Ile848Ile	synonymous_variant	Exon 24 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.2544T>C	p.Ile848Ile	synonymous_variant	Exon 24 of 32	1	NM_002465.4	ENSP00000354849.2
MYBPC1	ENST00000551300.5 link	c.2172T>C	p.Ile724Ile	synonymous_variant	Exon 25 of 32	1		ENSP00000447116.1

Frequencies

GnomAD3 genomes

AF:

0.952

AC:

144869

AN:

152166

Hom.:

69001

Cov.:

show subpopulations

Gnomad AFR

AF:

0.943

Gnomad AMI

AF:

0.831

Gnomad AMR

AF:

0.969

Gnomad ASJ

AF:

0.971

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.952

Gnomad FIN

AF:

0.956

Gnomad MID

AF:

0.981

Gnomad NFE

AF:

0.950

Gnomad OTH

AF:

0.955

GnomAD2 exomes

AF:

0.958

AC:

240827

AN:

251456

AF XY:

0.956

show subpopulations

Gnomad AFR exome

AF:

0.945

Gnomad AMR exome

AF:

0.977

Gnomad ASJ exome

AF:

0.974

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.957

Gnomad NFE exome

AF:

0.947

Gnomad OTH exome

AF:

0.953

GnomAD4 exome

AF:

0.952

AC:

1391438

AN:

1461566

Hom.:

662465

Cov.:

AF XY:

0.952

AC XY:

692100

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.944

AC:

31603

AN:

33474

American (AMR)

AF:

0.975

AC:

43619

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.971

AC:

25382

AN:

26132

East Asian (EAS)

AF:

1.00

AC:

39683

AN:

39690

South Asian (SAS)

AF:

0.953

AC:

82203

AN:

86244

European-Finnish (FIN)

AF:

0.955

AC:

50997

AN:

53420

Middle Eastern (MID)

AF:

0.965

AC:

5567

AN:

5768

European-Non Finnish (NFE)

AF:

0.949

AC:

1054547

AN:

1111728

Other (OTH)

AF:

0.958

AC:

57837

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

3716

7431

11147

14862

18578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21606

43212

64818

86424

108030

<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:

0.952

AC:

144980

AN:

152284

Hom.:

69053

Cov.:

AF XY:

0.953

AC XY:

70975

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.943

AC:

39198

AN:

41548

American (AMR)

AF:

0.970

AC:

14832

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.971

AC:

3373

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5180

AN:

5184

South Asian (SAS)

AF:

0.952

AC:

4592

AN:

4824

European-Finnish (FIN)

AF:

0.956

AC:

10143

AN:

10608

Middle Eastern (MID)

AF:

0.983

AC:

289

AN:

294

European-Non Finnish (NFE)

AF:

0.950

AC:

64596

AN:

68030

Other (OTH)

AF:

0.955

AC:

2021

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

361

721

1082

1442

1803

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.952

Hom.:

75054

Bravo

AF:

0.953

Asia WGS

AF:

0.980

AC:

3410

AN:

3478

EpiCase

AF:

0.952

EpiControl

AF:

0.950

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

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

- -

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 12, 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

-0.60

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

0.46

Mutation Taster

=93/7

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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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