rs387906658

Positions:

• chr12-101670362-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002465.4(MYBPC1):​c.2566T>C​(p.Tyr856His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC1 NM_002465.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.90

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC1	NM_002465.4	c.2566T>C	p.Tyr856His	missense_variant	24/32	ENST00000361466.7	NP_002456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC1	ENST00000361466.7	c.2566T>C	p.Tyr856His	missense_variant	24/32	1	NM_002465.4	ENSP00000354849	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arthrogryposis, distal, type 1B Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 11, 2018	The MYBPC1 c.2566T>C (p.Tyr856His) variant is a missense variant that has been reported in a heterozygous state in an individual with bilateral vertical talus and hand contractures (Gurnett et al. 2010). This individual's maternal grandfather, who showed bilateral clubfoot but no hand contractures, was also heterozygous for the variant; the genotype and phenotype of the mother are not described. The p.Tyr856His variant was absent from 400 control individuals and is not found in the 1000 Genomes Project, Exome Sequencing Project, Exome Aggregation Consortium, or Genome Aggregation Database. Functional studies revealed that the presence of the Tyr856His variant completely abolished all binding activity with native myosin and actin filaments (Ackermann et al. 2013) and altered phosphorylation in affected muscle (Ackermann et al. 2015) without altering the distribution of the protein along the thick filament (Vydyanath et al. 2012). In addition, injection of zebrafish embryos with Tyr856His mRNA adversely affected motor activity; resulted in slower muscle fibers, a significant reduction in motor excitation, and delayed hatching; and increased failure to survive past 10 days post-fertilization (Ha et al. 2013). The clinical evidence for this variant is limited. The p.Tyr856His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for distal arthrogryposis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	.;.;.;.;.;T;.;.;.;.;.;.;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.5	.;M;.;.;.;.;.;.;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.010	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;D;.;.;.;.;.;D
Vest4		0.82
MutPred		0.73		.;Gain of disorder (P = 0.0304);.;.;.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0304);
MVP		0.73
MPC		0.87
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.44
gMVP		0.76

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: rs387906658; hg19: chr12-102064140;