12-101595222-C-T

Position:

• chr12-101595222-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.25+127C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00849 in 905,520 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (40 hom.)
• Consequence: MYBPC1 NM_002465.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0800

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=-0.82).
• BP6: Variant 12-101595222-C-T is Benign according to our data. Variant chr12-101595222-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1212014.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 = 0.00648 (986/152070) while in subpopulation NFE AF= 0.0108 (736/67988). AF 95% confidence interval is 0.0102. There are 5 homozygotes in gnomad4. There are 443 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC1	NM_002465.4	c.25+127C>T		intron_variant		ENST00000361466.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC1	ENST00000361466.7	c.25+127C>T		intron_variant		1	NM_002465.4	A2

Frequencies

GnomAD3 genomes AF: 0.00649 AC: 986 AN: 151952 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00617

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00256

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00432

GnomAD4 exome AF: 0.00889 AC: 6701 AN: 753450 Hom.: 40 AF XY: 0.00879 AC XY: 3465 AN XY: 394004

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00519

Gnomad4 ASJ exome AF: 0.000608

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000324

Gnomad4 FIN exome AF: 0.00240

Gnomad4 NFE exome AF: 0.0120

Gnomad4 OTH exome AF: 0.00683

GnomAD4 genome AF: 0.00648 AC: 986 AN: 152070 Hom.: 5 Cov.: 32 AF XY: 0.00596 AC XY: 443 AN XY: 74316

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00616

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00256

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00980 Hom.: 0

Bravo AF: 0.00704

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.6
DANN	Benign	0.75

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: rs117213476; hg19: chr12-101989000;