13-77051811-C-T

Variant names:

• chr13-77051811-C-T
• rs117836900
• NM_015057.5:c.13755G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 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. 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
• Publications: 2 publications found

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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 13-77051811-C-T is Benign according to our data. Variant chr13-77051811-C-T is described in ClinVar as Benign. ClinVar VariationId 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. GnomAdExome4 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 GnomAdExome4. There are 7235 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1221 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015057.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYCBP2	NM_015057.5	MANE Select	c.13755G>A	p.Gln4585Gln	splice_region synonymous	Exon 81 of 83	NP_055872.4	O75592-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYCBP2	ENST00000544440.7	TSL:1 MANE Select	c.13755G>A	p.Gln4585Gln	splice_region synonymous	Exon 81 of 83	ENSP00000444596.2	O75592-1
	MYCBP2	ENST00000357337.11	TSL:1	c.13935G>A	p.Gln4645Gln	splice_region synonymous	Exon 82 of 84	ENSP00000349892.6	A0A499FJI4
	ENSG00000283208	ENST00000638147.2	TSL:5	c.566-23707C>T		intron	N/A	ENSP00000490953.2	A0A1B0GWJ7

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

GnomAD2 exomes AF: 0.00807 AC: 2026 AN: 251206 AF XY: 0.00826

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 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

African (AFR) AF: 0.00173 AC: 58 AN: 33438

American (AMR) AF: 0.00481 AC: 215 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 294 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00403 AC: 347 AN: 86028

European-Finnish (FIN) AF: 0.00326 AC: 174 AN: 53388

Middle Eastern (MID) AF: 0.0186 AC: 107 AN: 5762

European-Non Finnish (NFE) AF: 0.0117 AC: 12974 AN: 1109646

Other (OTH) AF: 0.00993 AC: 599 AN: 60298

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

African (AFR) AF: 0.00169 AC: 70 AN: 41522

American (AMR) AF: 0.00746 AC: 114 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4820

European-Finnish (FIN) AF: 0.00321 AC: 34 AN: 10600

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0135 AC: 919 AN: 67994

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.0118 Hom.: 14

Bravo AF: 0.00768

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0144

EpiControl AF: 0.0137

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	MYCBP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.78
PhyloP100		4.6
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs117836900; hg19: chr13-77625946; COSMIC: COSV99050314;