12-101614529-A-C

Position:

• chr12-101614529-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_002465.4(MYBPC1):​c.59A>C​(p.Glu20Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MYBPC1 NM_002465.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001129
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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]

LOC105369938 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12084681).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00000821 (12/1461358) while in subpopulation SAS AF= 0.000139 (12/86190). AF 95% confidence interval is 0.00008. There are 0 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC1	NM_002465.4	c.59A>C	p.Glu20Ala	missense_variant, splice_region_variant	2/32	ENST00000361466.7
LOC105369938	XR_001749279.2	n.722+25T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC1	ENST00000361466.7	c.59A>C	p.Glu20Ala	missense_variant, splice_region_variant	2/32	1	NM_002465.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 250366 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461358 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 726970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	.;.;.;T;.;.;.;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.60	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.;N;.;N;N;N;N;N
MutationTaster	Benign	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.38	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.058
Sift	Benign	0.092	T;T;T;T;T;T;T;D;T
Sift4G	Benign	0.37	T;T;T;T;T;T;T;T;T
Polyphen		0.0080, 0.030, 0.0050	.;.;B;B;B;.;.;.;B
Vest4		0.37
MutPred		0.25		Gain of catalytic residue at P17 (P = 5e-04);Gain of catalytic residue at P17 (P = 5e-04);Gain of catalytic residue at P17 (P = 5e-04);Gain of catalytic residue at P17 (P = 5e-04);Gain of catalytic residue at P17 (P = 5e-04);Gain of catalytic residue at P17 (P = 5e-04);Gain of catalytic residue at P17 (P = 5e-04);Gain of catalytic residue at P17 (P = 5e-04);Gain of catalytic residue at P17 (P = 5e-04);
MVP		0.43
MPC		0.20
ClinPred		0.11	T
GERP RS		2.7
Varity_R		0.042
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.13		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: rs762880331; hg19: chr12-102008307;