chr12-101642527-C-G

Variant names:

• chr12-101642527-C-G
• rs2293468
• NM_002465.4:c.774C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_002465.4(MYBPC1):​c.774C>G​(p.Asp258Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D258D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC1 NM_002465.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.819
• Publications: 17 publications found

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]

MYBPC1 Gene-Disease associations (from GenCC):

• arthrogryposis, distal, type 1B

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• myopathy, congenital, with tremor

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• lethal congenital contracture syndrome 4

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal congenital contracture syndrome 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_002465.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC1	NM_002465.4	c.774C>G	p.Asp258Glu	missense_variant	Exon 11 of 32	ENST00000361466.7	NP_002456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC1	ENST00000361466.7	c.774C>G	p.Asp258Glu	missense_variant	Exon 11 of 32	1	NM_002465.4	ENSP00000354849.2
MYBPC1	ENST00000551300.5	c.402C>G	p.Asp134Glu	missense_variant	Exon 12 of 32	1		ENSP00000447116.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 4125

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;.;.;.;.;T;.;.;.;.;.;.;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.6	.;H;.;.;.;.;H;H;.;.;.;.;H
PhyloP100		0.82
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99, 0.99	.;.;.;.;D;D;D;.;.;.;.;.;D
Vest4		0.72
MutPred		0.57		.;.;.;.;.;Gain of catalytic residue at Y242 (P = 0.0446);.;.;.;.;.;.;.;
MVP		0.96
MPC		2.2
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.63
gMVP		0.61
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs2293468; hg19: chr12-102036305;