chr15-40220705-A-G

Variant names:

• chr15-40220705-A-G
• rs35611758
• NM_001211.6:c.3099A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001211.6(BUB1B):​c.3099A>G​(p.Lys1033Lys) 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:6
• Conservation: PhyloP100: 1.91
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001211.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1B	NM_001211.6	MANE Select	c.3099A>G	p.Lys1033Lys	synonymous	Exon 23 of 23	NP_001202.5
	BUB1B-PAK6	NM_001128628.3		c.-201+3038A>G		intron	N/A	NP_001122100.1
	BUB1B-PAK6	NM_001128629.3		c.-118+3038A>G		intron	N/A	NP_001122101.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1B	ENST00000287598.11	TSL:1 MANE Select	c.3099A>G	p.Lys1033Lys	synonymous	Exon 23 of 23	ENSP00000287598.7
	BUB1B	ENST00000412359.7	TSL:2	c.3141A>G	p.Lys1047Lys	synonymous	Exon 23 of 23	ENSP00000398470.3
	BUB1B-PAK6	ENST00000559435.1	TSL:5	n.204A>G		non_coding_transcript_exon	Exon 2 of 6	ENSP00000457109.1

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

GnomAD2 exomes AF: 0.0212 AC: 5342 AN: 251486 AF XY: 0.0160

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 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

African (AFR) AF: 0.293 AC: 9795 AN: 33470

American (AMR) AF: 0.0148 AC: 664 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00566 AC: 148 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.0137 AC: 79 AN: 5768

European-Non Finnish (NFE) AF: 0.000911 AC: 1013 AN: 1112008

Other (OTH) AF: 0.0196 AC: 1183 AN: 60394

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

African (AFR) AF: 0.284 AC: 11795 AN: 41470

American (AMR) AF: 0.0281 AC: 429 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 68026

Other (OTH) AF: 0.0601 AC: 127 AN: 2112

Alfa AF: 0.0350 Hom.: 459

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35611758; hg19: chr15-40512906; COSMIC: COSV104598940;