12-101594996-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002465.4(MYBPC1):c.-75G>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 0.169 in 1,456,236 control chromosomes in the GnomAD database, including 22,723 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1847 hom., cov: 32)
  • Exomes 𝑓: 0.17 (20876 hom.)
• Consequence: MYBPC1 NM_002465.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.32

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=-0.8).
• BP6: Variant 12-101594996-G-T is Benign according to our data. Variant chr12-101594996-G-T is described in ClinVar as [Benign]. Clinvar id is 306704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101594996-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC1	NM_002465.4	c.-75G>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.-75G>T		5_prime_UTR_variant	1/32	1	NM_002465.4	A2

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20370 AN: 152004 Hom.: 1853 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.0692

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.173 AC: 226234 AN: 1304114 Hom.: 20876 Cov.: 18 AF XY: 0.176 AC XY: 115497 AN XY: 656962

Gnomad4 AFR exome AF: 0.0286

Gnomad4 AMR exome AF: 0.0959

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.178

GnomAD4 genome AF: 0.134 AC: 20354 AN: 152122 Hom.: 1847 Cov.: 32 AF XY: 0.134 AC XY: 9954 AN XY: 74354

Gnomad4 AFR AF: 0.0341

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.331

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.139

Alfa AF: 0.117 Hom.: 287

Bravo AF: 0.129

Asia WGS AF: 0.226 AC: 786 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

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	-0.80
Cadd	Benign	0.050
Dann	Benign	0.72

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

LitVar

Other links and lift over

dbSNP: rs1697477; hg19: chr12-101988774; COSMIC: COSV62258943; COSMIC: COSV62258943;