15-40217497-A-G

Variant names:

• chr15-40217497-A-G
• NM_001211.6:c.2680A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001211.6(BUB1B):​c.2680A>G​(p.Ile894Val) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BUB1B NM_001211.6 missense, splice_region
• Scores: Splicing: ADA: 0.8158
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.03

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35959446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BUB1B	NM_001211.6	c.2680A>G	p.Ile894Val	missense_variant, splice_region_variant	Exon 21 of 23	ENST00000287598.11	NP_001202.5
BUB1B-PAK6	NM_001128628.3	c.-371A>G		5_prime_UTR_variant	Exon 1 of 11		NP_001122100.1
BUB1B-PAK6	NM_001128629.3	c.-288A>G		5_prime_UTR_variant	Exon 1 of 10		NP_001122101.1
LOC107984763	XR_001751506.2	n.217+21988T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BUB1B	ENST00000287598.11	c.2680A>G	p.Ile894Val	missense_variant, splice_region_variant	Exon 21 of 23	1	NM_001211.6	ENSP00000287598.7
BUB1B	ENST00000412359.7	c.2722A>G	p.Ile908Val	missense_variant, splice_region_variant	Exon 21 of 23	2		ENSP00000398470.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I894V variant (also known as c.2680A>G), located in coding exon 21 of the BUB1B gene, results from an A to G substitution at nucleotide position 2680. The isoleucine at codon 894 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.056	T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.18
Sift	Benign	0.045	D;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.47
MutPred		0.49		Loss of stability (P = 0.1246);.;
MVP		0.77
MPC		0.46
ClinPred		0.84	D
GERP RS		5.7
Varity_R		0.093
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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: chr15-40509698; COSMIC: COSV99806953; COSMIC: COSV99806953;