15-40218503-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001211.6(BUB1B):​c.2898G>T​(p.Lys966Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

BUB1B
NM_001211.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.02
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BUB1BNM_001211.6 linkuse as main transcriptc.2898G>T p.Lys966Asn missense_variant 22/23 ENST00000287598.11 NP_001202.5
BUB1B-PAK6NM_001128628.3 linkuse as main transcriptc.-201+836G>T intron_variant NP_001122100.1
LOC107984763XR_001751506.2 linkuse as main transcriptn.217+20982C>A intron_variant, non_coding_transcript_variant
BUB1B-PAK6NM_001128629.3 linkuse as main transcriptc.-118+836G>T intron_variant NP_001122101.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BUB1BENST00000287598.11 linkuse as main transcriptc.2898G>T p.Lys966Asn missense_variant 22/231 NM_001211.6 ENSP00000287598 P1O60566-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 23, 2023The p.K966N variant (also known as c.2898G>T), located in coding exon 22 of the BUB1B gene, results from a G to T substitution at nucleotide position 2898. The lysine at codon 966 is replaced by asparagine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.069
T;.
Eigen
Benign
-0.20
Eigen_PC
Benign
-0.0065
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.67
T;T
M_CAP
Benign
0.0042
T
MetaRNN
Benign
0.21
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
L;.
MutationTaster
Benign
1.0
D;D;N;N
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
0.16
N;N
REVEL
Benign
0.054
Sift
Benign
0.46
T;T
Sift4G
Benign
0.11
T;T
Polyphen
0.0040
B;.
Vest4
0.24
MutPred
0.60
Loss of solvent accessibility (P = 0.0187);.;
MVP
0.76
MPC
0.23
ClinPred
0.48
T
GERP RS
3.9
Varity_R
0.067
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.30
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.30
Position offset: 13

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-40510704; API