13-77055554-A-T

Variant names:

• chr13-77055554-A-T
• rs200563433
• NM_015057.5:c.13647+4T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015057.5(MYCBP2):​c.13647+4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,612,264 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (6 hom.)
• Consequence: MYCBP2 NM_015057.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001324
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.22

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:):

MYCBP2-AS1 (HGNC:41023): (MYCBP2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 13-77055554-A-T is Benign according to our data. Variant chr13-77055554-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 718182.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 364 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYCBP2	NM_015057.5	c.13647+4T>A		splice_region_variant, intron_variant	Intron 80 of 82	ENST00000544440.7	NP_055872.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYCBP2	ENST00000544440.7	c.13647+4T>A		splice_region_variant, intron_variant	Intron 80 of 82	1	NM_015057.5	ENSP00000444596.2
ENSG00000283208	ENST00000638147.2	c.566-19964A>T		intron_variant	Intron 3 of 4	5		ENSP00000490953.2

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00220 AC: 546 AN: 248350 AF XY: 0.00222

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00428

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00178

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00264 AC: 3858 AN: 1459958 Hom.: 6 Cov.: 30 AF XY: 0.00262 AC XY: 1901 AN XY: 726344

Gnomad4 AFR exome AF: 0.000359 AC: 12 AN: 33458

Gnomad4 AMR exome AF: 0.00107 AC: 48 AN: 44684

Gnomad4 ASJ exome AF: 0.00387 AC: 101 AN: 26098

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39650

Gnomad4 SAS exome AF: 0.000569 AC: 49 AN: 86104

Gnomad4 FIN exome AF: 0.00187 AC: 99 AN: 52956

Gnomad4 NFE exome AF: 0.00305 AC: 3389 AN: 1110906

Gnomad4 Remaining exome AF: 0.00254 AC: 153 AN: 60340

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00213 AC XY: 159 AN XY: 74476

Gnomad4 AFR AF: 0.000481 AC: 0.000481047 AN: 0.000481047

Gnomad4 AMR AF: 0.00177 AC: 0.00176609 AN: 0.00176609

Gnomad4 ASJ AF: 0.00433 AC: 0.00433025 AN: 0.00433025

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000830 AC: 0.000829531 AN: 0.000829531

Gnomad4 FIN AF: 0.00104 AC: 0.00103559 AN: 0.00103559

Gnomad4 NFE AF: 0.00419 AC: 0.00418933 AN: 0.00418933

Gnomad4 OTH AF: 0.000473 AC: 0.000473485 AN: 0.000473485

Alfa AF: 0.00319 Hom.: 0

Bravo AF: 0.00234

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00350

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYCBP2-related disorder Benign:1

Feb 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	-0.72
CADD	Benign	16
DANN	Benign	0.69
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.048
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: rs200563433; hg19: chr13-77629689;