rs183524782

Positions:

• chr12-101634614-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002465.4(MYBPC1):​c.608+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,607,052 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (41 hom.)
• Consequence: MYBPC1 NM_002465.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.550

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=-0.7).
• BP6: Variant 12-101634614-A-G is Benign according to our data. Variant chr12-101634614-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 211546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101634614-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00425 (648/152380) while in subpopulation NFE AF= 0.00623 (424/68038). AF 95% confidence interval is 0.00574. There are 3 homozygotes in gnomad4. There are 340 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC1	NM_002465.4	c.608+9A>G		intron_variant		ENST00000361466.7	NP_002456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC1	ENST00000361466.7	c.608+9A>G		intron_variant		1	NM_002465.4	ENSP00000354849	A2

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 648 AN: 152262 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00549

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00623

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00405 AC: 1018 AN: 251252 Hom.: 6 AF XY: 0.00437 AC XY: 593 AN XY: 135822

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00235

Gnomad FIN exome AF: 0.00473

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00590 AC: 8585 AN: 1454672 Hom.: 41 Cov.: 28 AF XY: 0.00591 AC XY: 4278 AN XY: 724198

Gnomad4 AFR exome AF: 0.000841

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00356

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00261

Gnomad4 FIN exome AF: 0.00468

Gnomad4 NFE exome AF: 0.00682

Gnomad4 OTH exome AF: 0.00460

GnomAD4 genome AF: 0.00425 AC: 648 AN: 152380 Hom.: 3 Cov.: 31 AF XY: 0.00456 AC XY: 340 AN XY: 74524

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.00623

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00518 Hom.: 4

Bravo AF: 0.00420

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 04, 2015

- -

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	-0.70
CADD	Benign	9.1
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs183524782; hg19: chr12-102028392;