12-101595080-C-G

Position:

• chr12-101595080-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002465.4(MYBPC1):​c.10C>G​(p.Pro4Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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 U:1
• Conservation: PhyloP100: 5.37

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24840319).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC1	NM_002465.4	c.10C>G	p.Pro4Ala	missense_variant	1/32	ENST00000361466.7	NP_002456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC1	ENST00000361466.7	c.10C>G	p.Pro4Ala	missense_variant	1/32	1	NM_002465.4	ENSP00000354849	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2022

The c.10C>G (p.P4A) alteration is located in exon 1 (coding exon 1) of the MYBPC1 gene. This alteration results from a C to G substitution at nucleotide position 10, causing the proline (P) at amino acid position 4 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	.;.;.;.;.;T;.;.;.;.;.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T;D;T;T;D;D;D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.34	N;N;N;.;N;.;N;N;N;N;N;N
MutationTaster	Benign	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.2	N;N;D;N;N;N;N;N;N;D;N;N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;T;D;D;D;D;T;T;T;D;D;T
Sift4G	Benign	0.14	T;T;T;T;T;D;T;T;T;D;T;T
Polyphen		1.0, 0.019, 1.0	.;.;.;.;D;B;D;.;.;.;.;D
Vest4		0.28
MutPred		0.31		Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);Gain of catalytic residue at P2 (P = 5e-04);
MVP		0.54
MPC		0.050
ClinPred		0.83	D
GERP RS		5.9
Varity_R		0.084
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-101988858;