12-101594978-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.-93C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,236,734 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (9 hom., cov: 32)
  • Exomes 𝑓: 0.010 (76 hom.)
• Consequence: MYBPC1 NM_002465.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.669

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 12-101594978-C-T is Benign according to our data. Variant chr12-101594978-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 306703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00768 (1170/152264) while in subpopulation NFE AF= 0.0119 (806/68014). AF 95% confidence interval is 0.0112. There are 9 homozygotes in gnomad4. There are 529 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC1	NM_002465.4	c.-93C>T		5_prime_UTR_variant	1/32	ENST00000361466.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC1	ENST00000361466.7	c.-93C>T		5_prime_UTR_variant	1/32	1	NM_002465.4	A2

Frequencies

GnomAD3 genomes AF: 0.00769 AC: 1170 AN: 152146 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00956

GnomAD4 exome AF: 0.0105 AC: 11377 AN: 1084470 Hom.: 76 Cov.: 14 AF XY: 0.0100 AC XY: 5563 AN XY: 554326

Gnomad4 AFR exome AF: 0.00187

Gnomad4 AMR exome AF: 0.00421

Gnomad4 ASJ exome AF: 0.0345

Gnomad4 EAS exome AF: 0.000398

Gnomad4 SAS exome AF: 0.000690

Gnomad4 FIN exome AF: 0.00183

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.00768 AC: 1170 AN: 152264 Hom.: 9 Cov.: 32 AF XY: 0.00710 AC XY: 529 AN XY: 74458

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.00563

Gnomad4 ASJ AF: 0.0383

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00760

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 30, 2019

- -

Arthrogryposis, distal, type 1B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.49
Cadd	Benign	9.0
Dann	Benign	0.82

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs78173516; hg19: chr12-101988756;