15-40220617-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001211.6(BUB1B):​c.3011A>G​(p.Asn1004Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000603 in 1,614,218 control chromosomes in the GnomAD database, including 5 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00033 ( 3 hom. )

Consequence

BUB1B
NM_001211.6 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 1.67
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-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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0036415458).
BP6
Variant 15-40220617-A-G is Benign according to our data. Variant chr15-40220617-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 133772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00323 (492/152342) while in subpopulation AFR AF= 0.0113 (471/41582). AF 95% confidence interval is 0.0105. There are 2 homozygotes in gnomad4. There are 230 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BUB1BNM_001211.6 linkc.3011A>G p.Asn1004Ser missense_variant Exon 23 of 23 ENST00000287598.11 NP_001202.5 O60566-1
BUB1B-PAK6NM_001128628.3 linkc.-201+2950A>G intron_variant Intron 1 of 10 NP_001122100.1 Q9NQU5-1A0A024R9Q4
BUB1B-PAK6NM_001128629.3 linkc.-118+2950A>G intron_variant Intron 1 of 9 NP_001122101.1 Q9NQU5-1A0A024R9Q4
LOC107984763XR_001751506.2 linkn.217+18868T>C intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BUB1BENST00000287598.11 linkc.3011A>G p.Asn1004Ser missense_variant Exon 23 of 23 1 NM_001211.6 ENSP00000287598.7 O60566-1
BUB1BENST00000412359.7 linkc.3053A>G p.Asn1018Ser missense_variant Exon 23 of 23 2 ENSP00000398470.3 O60566-3
BUB1B-PAK6ENST00000559435.1 linkn.116A>G non_coding_transcript_exon_variant Exon 2 of 6 5 ENSP00000457109.1 H3BTB9

Frequencies

GnomAD3 genomes
AF:
0.00321
AC:
488
AN:
152224
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0113
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000785
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:
0.0000147
Gnomad OTH
AF:
0.00382
GnomAD3 exomes
AF:
0.000780
AC:
196
AN:
251434
Hom.:
0
AF XY:
0.000611
AC XY:
83
AN XY:
135892
show subpopulations
Gnomad AFR exome
AF:
0.0111
Gnomad AMR exome
AF:
0.000231
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:
0.0000176
Gnomad OTH exome
AF:
0.000815
GnomAD4 exome
AF:
0.000330
AC:
482
AN:
1461876
Hom.:
3
Cov.:
31
AF XY:
0.000261
AC XY:
190
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0111
Gnomad4 AMR exome
AF:
0.000358
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000450
Gnomad4 OTH exome
AF:
0.000679
GnomAD4 genome
AF:
0.00323
AC:
492
AN:
152342
Hom.:
2
Cov.:
32
AF XY:
0.00309
AC XY:
230
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.0113
Gnomad4 AMR
AF:
0.000784
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00378
Alfa
AF:
0.000498
Hom.:
0
Bravo
AF:
0.00376
ESP6500AA
AF:
0.00908
AC:
40
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000923
AC:
112
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
May 20, 2019
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Inborn genetic diseases Benign:1
Aug 27, 2021
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Colorectal cancer Benign:1
Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Premature chromatid separation trait Benign:1
Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mosaic variegated aneuploidy syndrome 1 Benign:1
Dec 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Other:1
Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.048
BayesDel_addAF
Benign
-0.67
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
14
DANN
Benign
0.76
DEOGEN2
Benign
0.074
T;.
Eigen
Benign
-0.95
Eigen_PC
Benign
-0.68
FATHMM_MKL
Benign
0.37
N
LIST_S2
Benign
0.65
T;T
MetaRNN
Benign
0.0036
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
-0.90
N;.
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.30
N;N
REVEL
Benign
0.029
Sift
Benign
0.76
T;T
Sift4G
Benign
0.81
T;T
Polyphen
0.0
B;.
Vest4
0.049
MVP
0.35
MPC
0.15
ClinPred
0.00088
T
GERP RS
2.0
Varity_R
0.015
gMVP
0.022

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

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

Other links and lift over

dbSNP: rs34998711; hg19: chr15-40512818; API