rs35611758

Positions:

• chr15-40220705-A-C
• chr15-40220705-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001211.6(BUB1B):​c.3099A>C​(p.Lys1033Asn) 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1033R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91

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:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22519445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BUB1B	NM_001211.6	c.3099A>C	p.Lys1033Asn	missense_variant	23/23	ENST00000287598.11
BUB1B-PAK6	NM_001128628.3	c.-201+3038A>C		intron_variant
LOC107984763	XR_001751506.2	n.217+18780T>G		intron_variant, non_coding_transcript_variant
BUB1B-PAK6	NM_001128629.3	c.-118+3038A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BUB1B	ENST00000287598.11	c.3099A>C	p.Lys1033Asn	missense_variant	23/23	1	NM_001211.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	0.021
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.037
Sift	Benign	0.12	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.65	P;.
Vest4		0.23
MutPred		0.37		Loss of helix (P = 0.0376);.;
MVP		0.82
MPC		0.33
ClinPred		0.59	D
GERP RS		5.3
Varity_R		0.10
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35611758; hg19: chr15-40512906;