Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001211.6(BUB1B):c.2996G>T(p.Arg999Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R999W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

BUB1B
NM_001211.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.57

Publications

0 publications found

Variant links:

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 links:

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]

BUB1B-PAK6 links:

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]

PAK6 links:

LOC107984763 (HGNC:):

LOC107984763 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BUB1B	NM_001211.6	MANE Select	c.2996G>T	p.Arg999Leu	missense	Exon 23 of 23	NP_001202.5
BUB1B-PAK6	NM_001128628.3		c.-201+2935G>T		intron	N/A	NP_001122100.1
BUB1B-PAK6	NM_001128629.3		c.-118+2935G>T		intron	N/A	NP_001122101.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BUB1B	ENST00000287598.11	TSL:1 MANE Select	c.2996G>T	p.Arg999Leu	missense	Exon 23 of 23	ENSP00000287598.7
BUB1B	ENST00000412359.7	TSL:2	c.3038G>T	p.Arg1013Leu	missense	Exon 23 of 23	ENSP00000398470.3
BUB1B-PAK6	ENST00000559435.1	TSL:5	n.101G>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000457109.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

1.6

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.3

REVEL

Benign

0.20

Sift

Uncertain

0.014

Sift4G

Uncertain

0.010

Polyphen

0.93

Vest4

0.61

MutPred

0.58

Loss of solvent accessibility (P = 0.1077)

MVP

0.71

MPC

0.76

ClinPred

0.83

GERP RS

5.0

Varity_R

0.14

gMVP

0.39

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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15-40220602-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over