rs61935677

chr12-101632148-C-Gchr12-101632148-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002465.4(MYBPC1):c.556+10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,563,424 control chromosomes in the GnomAD database, including 33,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3278 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30704 hom.)
• Consequence: MYBPC1 NM_002465.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.167

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-101632148-C-G is Benign according to our data. Variant chr12-101632148-C-G is described in ClinVar as [Benign]. Clinvar id is 129646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101632148-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC1	NM_002465.4	c.556+10C>G		intron_variant		ENST00000361466.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC1	ENST00000361466.7	c.556+10C>G		intron_variant		1	NM_002465.4	A2

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30849 AN: 151904 Hom.: 3280 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.274

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.216

GnomAD3 exomes AF: 0.187 AC: 47004 AN: 251438 Hom.: 4971 AF XY: 0.194 AC XY: 26394 AN XY: 135894

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.282

Gnomad EAS exome AF: 0.0845

Gnomad SAS exome AF: 0.258

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.204 AC: 287531 AN: 1411402 Hom.: 30704 Cov.: 26 AF XY: 0.206 AC XY: 145542 AN XY: 705034

Gnomad4 AFR exome AF: 0.230

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.0874

Gnomad4 SAS exome AF: 0.260

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.213

GnomAD4 genome AF: 0.203 AC: 30854 AN: 152022 Hom.: 3278 Cov.: 32 AF XY: 0.198 AC XY: 14697 AN XY: 74314

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.286

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.255

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.205

Gnomad4 OTH AF: 0.217

Alfa AF: 0.154 Hom.: 431

Bravo AF: 0.205

Asia WGS AF: 0.166 AC: 577 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Arthrogryposis, distal, type 1B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.0
Dann	Benign	0.51

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: rs61935677; hg19: chr12-102025926; COSMIC: COSV62253354; COSMIC: COSV62253354;