rs1555242493

Positions:

• chr12-101653159-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_002465.4(MYBPC1):​c.1678G>C​(p.Val560Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC1 NM_002465.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.52

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-101653159-G-C is Pathogenic according to our data. Variant chr12-101653159-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523451.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC1	NM_002465.4	c.1678G>C	p.Val560Leu	missense_variant	18/32	ENST00000361466.7	NP_002456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC1	ENST00000361466.7	c.1678G>C	p.Val560Leu	missense_variant	18/32	1	NM_002465.4	ENSP00000354849.2
MYBPC1	ENST00000551300.5	c.1306G>C	p.Val436Leu	missense_variant	19/32	1		ENSP00000447116.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Distal arthrogryposis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	.;.;.;.;.;T;.;.;.;.;.;.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.6	.;L;.;.;.;.;L;L;.;.;.;.;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.031	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.034	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;D;.;D;.;.;.;.;.;D
Vest4		0.59
MutPred		0.67		.;Gain of sheet (P = 0.0827);.;.;.;.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;.;.;Gain of sheet (P = 0.0827);
MVP		0.64
MPC		0.70
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.23
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555242493; hg19: chr12-102046937;