12-101651253-A-T

Variant names:

• chr12-101651253-A-T
• rs825045
• NM_002465.4:c.1386A>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.340

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]

ENSG00000257514 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 129641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101651253-A-T is described in Lovd as [Benign].
• 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	c.1386A>T	p.Thr462Thr	synonymous_variant	Exon 16 of 32	ENST00000361466.7	NP_002456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC1	ENST00000361466.7	c.1386A>T	p.Thr462Thr	synonymous_variant	Exon 16 of 32	1	NM_002465.4	ENSP00000354849.2
MYBPC1	ENST00000551300.5	c.1014A>T	p.Thr338Thr	synonymous_variant	Exon 17 of 32	1		ENSP00000447116.1

Frequencies

GnomAD3 genomes AF: 0.0861 AC: 13081 AN: 151972 Hom.: 823 Cov.: 32

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

GnomAD3 exomes AF: 0.0541 AC: 13616 AN: 251460 Hom.: 540 AF XY: 0.0529 AC XY: 7188 AN XY: 135904

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 SAS exome AF: 0.0471

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.: 32 AF XY: 0.0545 AC XY: 39600 AN XY: 727188

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.0354

Gnomad4 ASJ exome AF: 0.0291

Gnomad4 EAS exome AF: 0.00264

Gnomad4 SAS exome AF: 0.0475

Gnomad4 FIN exome AF: 0.0471

Gnomad4 NFE exome AF: 0.0554

Gnomad4 OTH exome AF: 0.0531

GnomAD4 genome AF: 0.0861 AC: 13093 AN: 152090 Hom.: 822 Cov.: 32 AF XY: 0.0833 AC XY: 6194 AN XY: 74348

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.0494

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.0477

Gnomad4 FIN AF: 0.0461

Gnomad4 NFE AF: 0.0548

Gnomad4 OTH AF: 0.0750

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

Submissions by phenotype

not specified Benign:4

-

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

- -

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 31, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DANN	Benign	0.71

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

LitVar

Other links and lift over

dbSNP: rs825045; hg19: chr12-102045031;