rs1802286

Variant names:

• chr15-40218461-C-T
• rs1802286
• NM_001211.6:c.2856C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001211.6(BUB1B):​c.2856C>T​(p.Asp952Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,610,922 control chromosomes in the GnomAD database, including 653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (57 hom., cov: 32)
  • Exomes 𝑓: 0.026 (596 hom.)
• Consequence: BUB1B NM_001211.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.77
• Publications: 9 publications found

Genes affected

BUB1B (HGNC:1149): (BUB1 mitotic checkpoint serine/threonine kinase B) This gene encodes a kinase involved in spindle checkpoint function. The protein has been localized to the kinetochore and plays a role in the inhibition of the anaphase-promoting complex/cyclosome (APC/C), delaying the onset of anaphase and ensuring proper chromosome segregation. Impaired spindle checkpoint function has been found in many forms of cancer. [provided by RefSeq, Jul 2008]

BUB1B-PAK6 (HGNC:52276): (BUB1B-PAK6 readthrough) This gene represents readthrough transcription between the genes BUB1B (mitotic checkpoint serine/threonine-protein kinase BUB1 beta) and PAK6 (serine/threonine-protein kinase PAK 6). The protein encoded by the readthrough transcripts is the same as the product of the downstream gene (PAK6). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

PAK6 (HGNC:16061): (p21 (RAC1) activated kinase 6) This gene encodes a member of a family of p21-stimulated serine/threonine protein kinases, which contain an amino-terminal Cdc42/Rac interactive binding (CRIB) domain and a carboxyl-terminal kinase domain. These kinases function in a number of cellular processes, including cytoskeleton rearrangement, apoptosis, and the mitogen-activated protein (MAP) kinase signaling pathway. The protein encoded by this gene interacts with androgen receptor (AR) and translocates to the nucleus, where it is involved in transcriptional regulation. Changes in expression of this gene have been linked to prostate cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

LOC107984763 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 15-40218461-C-T is Benign according to our data. Variant chr15-40218461-C-T is described in ClinVar as Benign. ClinVar VariationId is 224924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0218 (3316/152282) while in subpopulation NFE AF = 0.0305 (2072/68024). AF 95% confidence interval is 0.0294. There are 57 homozygotes in GnomAd4. There are 1693 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 57 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001211.6. 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
	BUB1B	NM_001211.6	MANE Select	c.2856C>T	p.Asp952Asp	synonymous	Exon 22 of 23	NP_001202.5
	BUB1B-PAK6	NM_001128628.3		c.-201+794C>T		intron	N/A	NP_001122100.1
	BUB1B-PAK6	NM_001128629.3		c.-118+794C>T		intron	N/A	NP_001122101.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1B	ENST00000287598.11	TSL:1 MANE Select	c.2856C>T	p.Asp952Asp	synonymous	Exon 22 of 23	ENSP00000287598.7	O60566-1
	BUB1B	ENST00000412359.7	TSL:2	c.2898C>T	p.Asp966Asp	synonymous	Exon 22 of 23	ENSP00000398470.3	O60566-3
	BUB1B	ENST00000918306.1		c.2958C>T	p.Asp986Asp	synonymous	Exon 23 of 24	ENSP00000588365.1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3315 AN: 152164 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.00509

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00897

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0305

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0237 AC: 5928 AN: 250472 AF XY: 0.0240

Gnomad AFR exome AF: 0.00481

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.0308

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0613

Gnomad NFE exome AF: 0.0290

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0257 AC: 37498 AN: 1458640 Hom.: 596 Cov.: 30 AF XY: 0.0257 AC XY: 18632 AN XY: 725728

African (AFR) AF: 0.00413 AC: 138 AN: 33436

American (AMR) AF: 0.0129 AC: 576 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 782 AN: 26090

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39664

South Asian (SAS) AF: 0.0121 AC: 1044 AN: 86042

European-Finnish (FIN) AF: 0.0583 AC: 3113 AN: 53378

Middle Eastern (MID) AF: 0.0205 AC: 118 AN: 5762

European-Non Finnish (NFE) AF: 0.0273 AC: 30280 AN: 1109290

Other (OTH) AF: 0.0240 AC: 1445 AN: 60290

GnomAD4 genome AF: 0.0218 AC: 3316 AN: 152282 Hom.: 57 Cov.: 32 AF XY: 0.0227 AC XY: 1693 AN XY: 74446

African (AFR) AF: 0.00508 AC: 211 AN: 41562

American (AMR) AF: 0.00896 AC: 137 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4828

European-Finnish (FIN) AF: 0.0651 AC: 689 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0305 AC: 2072 AN: 68024

Other (OTH) AF: 0.0213 AC: 45 AN: 2114

Alfa AF: 0.0280 Hom.: 55

Bravo AF: 0.0173

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.0338

EpiControl AF: 0.0297

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Colorectal cancer (1)
-	-	1	Mosaic variegated aneuploidy syndrome 1 (1)
-	-	1	Premature chromatid separation trait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.3
DANN	Benign	0.76
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1802286; hg19: chr15-40510662; COSMIC: COSV55012097;