13-77051811-C-T

Position:

• chr13-77051811-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_015057.5(MYCBP2):​c.13755G>A​(p.Gln4585Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00992 in 1,611,182 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (9 hom., cov: 32)
  • Exomes 𝑓: 0.010 (123 hom.)
• Consequence: MYCBP2 NM_015057.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.57

Genes affected

MYCBP2 (HGNC:23386): (MYC binding protein 2) This gene encodes an E3 ubiquitin-protein ligase and member of the PHR (Phr1/MYCBP2, highwire and RPM-1) family of proteins. The encoded protein plays a role in axon guidance and synapse formation in the developing nervous system. In mammalian cells, this protein regulates the cAMP and mTOR signaling pathways, and may additionally regulate autophagy. Reduced expression of this gene has been observed in acute lymphoblastic leukemia patients and a mutation in this gene has been identified in patients with a rare inherited vision defect. [provided by RefSeq, Mar 2017]

ENSG00000283208 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 13-77051811-C-T is Benign according to our data. Variant chr13-77051811-C-T is described in ClinVar as [Benign]. Clinvar id is 775345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0101 (14768/1459002) while in subpopulation MID AF= 0.0186 (107/5762). AF 95% confidence interval is 0.0157. There are 123 homozygotes in gnomad4_exome. There are 7235 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1221 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYCBP2	NM_015057.5	c.13755G>A	p.Gln4585Gln	splice_region_variant, synonymous_variant	81/83	ENST00000544440.7	NP_055872.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYCBP2	ENST00000544440.7	c.13755G>A	p.Gln4585Gln	splice_region_variant, synonymous_variant	81/83	1	NM_015057.5	ENSP00000444596.2
ENSG00000283208	ENST00000638147.2	c.566-23707C>T		intron_variant		5		ENSP00000490953.2

Frequencies

GnomAD3 genomes AF: 0.00801 AC: 1218 AN: 152062 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00321

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00807 AC: 2026 AN: 251206 Hom.: 14 AF XY: 0.00826 AC XY: 1121 AN XY: 135774

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00415

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0101 AC: 14768 AN: 1459002 Hom.: 123 Cov.: 29 AF XY: 0.00997 AC XY: 7235 AN XY: 725954

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00481

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00403

Gnomad4 FIN exome AF: 0.00326

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.00993

GnomAD4 genome AF: 0.00802 AC: 1221 AN: 152180 Hom.: 9 Cov.: 32 AF XY: 0.00743 AC XY: 553 AN XY: 74384

Gnomad4 AFR AF: 0.00169

Gnomad4 AMR AF: 0.00746

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00321

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0108 Hom.: 3

Bravo AF: 0.00768

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0144

EpiControl AF: 0.0137

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

MYCBP2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.10		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: rs117836900; hg19: chr13-77625946; COSMIC: COSV99050314;