rs1801528

Positions:

• chr15-40206302-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001211.6(BUB1B):​c.1853T>C​(p.Val618Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,614,076 control chromosomes in the GnomAD database, including 2,953 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (1553 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (1400 hom.)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.782

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]

LOC107984763 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025277436).
• BP6: Variant 15-40206302-T-C is Benign according to our data. Variant chr15-40206302-T-C is described in ClinVar as [Benign]. Clinvar id is 133769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BUB1B	NM_001211.6	c.1853T>C	p.Val618Ala	missense_variant	15/23	ENST00000287598.11	NP_001202.5
LOC107984763	XR_001751506.2	n.218-26101A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BUB1B	ENST00000287598.11	c.1853T>C	p.Val618Ala	missense_variant	15/23	1	NM_001211.6	ENSP00000287598.7
BUB1B	ENST00000412359.7	c.1895T>C	p.Val632Ala	missense_variant	15/23	2		ENSP00000398470.3
BUB1B	ENST00000558972.1	n.*28T>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0788 AC: 11988 AN: 152084 Hom.: 1542 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.0593

GnomAD3 exomes AF: 0.0204 AC: 5140 AN: 251470 Hom.: 608 AF XY: 0.0154 AC XY: 2095 AN XY: 135910

Gnomad AFR exome AF: 0.274

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00854 AC: 12478 AN: 1461874 Hom.: 1400 Cov.: 31 AF XY: 0.00744 AC XY: 5411 AN XY: 727236

Gnomad4 AFR exome AF: 0.281

Gnomad4 AMR exome AF: 0.0144

Gnomad4 ASJ exome AF: 0.00566

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000908

Gnomad4 OTH exome AF: 0.0188

GnomAD4 genome AF: 0.0791 AC: 12034 AN: 152202 Hom.: 1553 Cov.: 32 AF XY: 0.0764 AC XY: 5690 AN XY: 74432

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.0271

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.0587

Alfa AF: 0.0186 Hom.: 570

Bravo AF: 0.0898

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.254 AC: 1117

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.0251 AC: 3045

Asia WGS AF: 0.0160 AC: 58 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00184

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Colorectal cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Mosaic variegated aneuploidy syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.069	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.65	N;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.4	N;N
REVEL	Benign	0.066
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.11
MPC		0.24
ClinPred		0.0010	T
GERP RS		-0.49
Varity_R		0.026
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1801528; hg19: chr15-40498503; COSMIC: COSV104598938; COSMIC: COSV104598938;