15-40220705-A-G

Position:

• chr15-40220705-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001211.6(BUB1B):​c.3099A>G​(p.Lys1033=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,614,064 control chromosomes in the GnomAD database, including 3,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (1688 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (1525 hom.)
• Consequence: BUB1B NM_001211.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 15-40220705-A-G is Benign according to our data. Variant chr15-40220705-A-G is described in ClinVar as [Benign]. Clinvar id is 257638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.91 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BUB1B	NM_001211.6	c.3099A>G	p.Lys1033=	synonymous_variant	23/23	ENST00000287598.11
BUB1B-PAK6	NM_001128628.3	c.-201+3038A>G		intron_variant
LOC107984763	XR_001751506.2	n.217+18780T>C		intron_variant, non_coding_transcript_variant
BUB1B-PAK6	NM_001128629.3	c.-118+3038A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BUB1B	ENST00000287598.11	c.3099A>G	p.Lys1033=	synonymous_variant	23/23	1	NM_001211.6	P1

Frequencies

GnomAD3 genomes AF: 0.0816 AC: 12416 AN: 152082 Hom.: 1673 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0282

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.0608

GnomAD3 exomes AF: 0.0212 AC: 5342 AN: 251486 Hom.: 654 AF XY: 0.0160 AC XY: 2177 AN XY: 135916

Gnomad AFR exome AF: 0.286

Gnomad AMR exome AF: 0.0123

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00885 AC: 12932 AN: 1461864 Hom.: 1525 Cov.: 31 AF XY: 0.00774 AC XY: 5627 AN XY: 727232

Gnomad4 AFR exome AF: 0.293

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.00566

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000911

Gnomad4 OTH exome AF: 0.0196

GnomAD4 genome AF: 0.0819 AC: 12468 AN: 152200 Hom.: 1688 Cov.: 32 AF XY: 0.0795 AC XY: 5915 AN XY: 74428

Gnomad4 AFR AF: 0.284

Gnomad4 AMR AF: 0.0281

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.0601

Alfa AF: 0.0337 Hom.: 352

Bravo AF: 0.0930

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Colorectal cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 24, 2019

- -

Mosaic variegated aneuploidy syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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; COSMIC: COSV104598940; COSMIC: COSV104598940;