12-101614487-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002465.4(MYBPC1):c.26-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,613,710 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (15 hom., cov: 32)
  • Exomes 𝑓: 0.012 (140 hom.)
• Consequence: MYBPC1 NM_002465.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002864
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.237

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 12-101614487-C-T is Benign according to our data. Variant chr12-101614487-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101614487-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0093 (1417/152310) while in subpopulation NFE AF= 0.0123 (837/68022). AF 95% confidence interval is 0.0116. There are 15 homozygotes in gnomad4. There are 643 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC1	NM_002465.4	c.26-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000361466.7
LOC105369938	XR_001749279.2	n.722+67G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC1	ENST00000361466.7	c.26-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002465.4	A2

Frequencies

GnomAD3 genomes AF: 0.00931 AC: 1417 AN: 152192 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.0596

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0102 AC: 2567 AN: 250704 Hom.: 30 AF XY: 0.0108 AC XY: 1462 AN XY: 135530

Gnomad AFR exome AF: 0.00241

Gnomad AMR exome AF: 0.00945

Gnomad ASJ exome AF: 0.0543

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00402

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0119 AC: 17356 AN: 1461400 Hom.: 140 Cov.: 30 AF XY: 0.0118 AC XY: 8589 AN XY: 727012

Gnomad4 AFR exome AF: 0.00379

Gnomad4 AMR exome AF: 0.00956

Gnomad4 ASJ exome AF: 0.0545

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00465

Gnomad4 FIN exome AF: 0.000769

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.00930 AC: 1417 AN: 152310 Hom.: 15 Cov.: 32 AF XY: 0.00863 AC XY: 643 AN XY: 74474

Gnomad4 AFR AF: 0.00281

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.0596

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0134 Hom.: 14

Bravo AF: 0.00977

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Arthrogryposis, distal, type 1B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	16
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs181619118; hg19: chr12-102008265;