15-40217580-G-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001211.6(BUB1B):c.2763G>C(p.Gln921His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

BUB1B
NM_001211.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:1O:1

Conservation

PhyloP100: 1.13

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21387008).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000302 (46/152168) while in subpopulation NFE AF= 0.000573 (39/68034). AF 95% confidence interval is 0.000431. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BUB1B	NM_001211.6 link	c.2763G>C	p.Gln921His	missense_variant	Exon 21 of 23	ENST00000287598.11	NP_001202.5	O60566-1
BUB1B-PAK6	NM_001128628.3 link	c.-288G>C		5_prime_UTR_variant	Exon 1 of 11		NP_001122100.1	Q9NQU5-1A0A024R9Q4
BUB1B-PAK6	NM_001128629.3 link	c.-205G>C		5_prime_UTR_variant	Exon 1 of 10		NP_001122101.1	Q9NQU5-1A0A024R9Q4
LOC107984763	XR_001751506.2 link	n.217+21905C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BUB1B	ENST00000287598.11 link	c.2763G>C	p.Gln921His	missense_variant	Exon 21 of 23	1	NM_001211.6	ENSP00000287598.7		O60566-1
BUB1B	ENST00000412359.7 link	c.2805G>C	p.Gln935His	missense_variant	Exon 21 of 23	2		ENSP00000398470.3		O60566-3

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251460

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000205

AC:

299

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

169

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000260

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000302

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000573

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000293

Hom.:

Bravo

AF:

0.000242

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mosaic variegated aneuploidy syndrome 1

Pathogenic:1Uncertain:3

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 03, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BUB1B c.2763G>C (p.Gln921His) missense variant has a maximum subpopulation frequency of 0.034% in gnomAD v2.1.1. This variant has been reported in a patient with clinical features of mosaic variegated aneuploidy syndrome including IUGR, microcephaly, cryptochidism, and embryonal rhabdomyosarcoma of the palate (PMID: 15475955). The variant was found to be maternally inherited along with a second BUB1B missense variant; the patient had a paternally inherited truncating variant in BUB1B. This variant has been reported as heterozygous in adults with various cancers including glioblastoma, lung squamous cell carcinoma, skin cutaneous melanoma, and uterine corpus endometrial carcinoma (PMID: 29625052, 36451132). The in silico tool REVEL predicts a benign effect on protein function, and the variant behaved similar to the wild-type in functional studies (PMID: 20516114). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 921 of the BUB1B protein (p.Gln921His). This variant is present in population databases (rs28989183, gnomAD 0.04%). This missense change has been observed in individual(s) with mosaic variegated aneuploidy, pancreatic cancer, lung cancer, endometrial cancer, glioblastoma, and melanoma (PMID: 15475955, 18548531, 28767289, 29625052, 36451132). ClinVar contains an entry for this variant (Variation ID: 6762). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect BUB1B function (PMID: 20516114). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1Benign:1

Dec 31, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with mosaic variegated aneuploidy and in individuals with pancreatic cancer and breast and/or ovarian cancer (Hanks 2004, Garca-Castillo 2008, Maxwell 2016, Shindo 2017); Published functional studies demonstrate no damaging effect: normal protein levels and functionality (Suijkerbuijk 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29625052, 18548531, 28767289, 27153395, 15475955, 20516114) -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BUB1B: BP4 -

Inborn genetic diseases

Uncertain:1

Apr 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2763G>C (p.Q921H) alteration is located in exon 21 (coding exon 21) of the BUB1B gene. This alteration results from a G to C substitution at nucleotide position 2763, causing the glutamine (Q) at amino acid position 921 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Colorectal cancer;C1850343:Mosaic variegated aneuploidy syndrome 1;C1864389:Premature chromatid separation trait

Uncertain:1

Jun 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Premature chromatid separation trait

Other:1

Nov 01, 2004

OMIM

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.068

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.60

T;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.24

Sift

Benign

0.57

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.99

D;.

Vest4

0.39

MutPred

0.68

Loss of solvent accessibility (P = 0.0364);.;

MVP

0.79

MPC

0.21

ClinPred

0.10

GERP RS

3.8

Varity_R

0.030

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over