rs764291

chr12-101675299-A-G

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.2817A>G(p.Pro939=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.05

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr12-101675299-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
MYBPC1	NM_002465.4	c.2817A>G	p.Pro939=	synonymous_variant	26/32	ENST00000361466.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC1	ENST00000361466.7	c.2817A>G	p.Pro939=	synonymous_variant	26/32	1	NM_002465.4	A2

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31184 AN: 152096 Hom.: 3757 Cov.: 32

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

GnomAD3 exomes AF: 0.223 AC: 55979 AN: 250936 Hom.: 7089 AF XY: 0.231 AC XY: 31339 AN XY: 135588

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 SAS exome AF: 0.227

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.: 38 AF XY: 0.265 AC XY: 192720 AN XY: 726966

Gnomad4 AFR exome AF: 0.0727

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.302

Gnomad4 EAS exome AF: 0.0893

Gnomad4 SAS exome AF: 0.230

Gnomad4 FIN exome AF: 0.263

Gnomad4 NFE exome AF: 0.284

Gnomad4 OTH exome AF: 0.257

GnomAD4 genome AF: 0.205 AC: 31177 AN: 152216 Hom.: 3755 Cov.: 32 AF XY: 0.203 AC XY: 15080 AN XY: 74428

Gnomad4 AFR AF: 0.0766

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.279

Gnomad4 OTH AF: 0.216

Alfa AF: 0.259 Hom.: 10240

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Arthrogryposis, distal, type 1B Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Myopathy, congenital, with tremor Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Lethal congenital contracture syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	3.3
Dann	Benign	0.59

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

LitVar

Other links and lift over

dbSNP: rs764291; hg19: chr12-102069077; COSMIC: COSV62251503; COSMIC: COSV62251503;