chr15-40220617-A-G

Variant names:

• chr15-40220617-A-G
• rs34998711
• NM_001211.6:c.3011A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1004D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.67
• 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 -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.3011A>G	p.Asn1004Ser	missense	Exon 23 of 23	NP_001202.5
	BUB1B-PAK6	NM_001128628.3		c.-201+2950A>G		intron	N/A	NP_001122100.1
	BUB1B-PAK6	NM_001128629.3		c.-118+2950A>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.3011A>G	p.Asn1004Ser	missense	Exon 23 of 23	ENSP00000287598.7
	BUB1B	ENST00000412359.7	TSL:2	c.3053A>G	p.Asn1018Ser	missense	Exon 23 of 23	ENSP00000398470.3
	BUB1B-PAK6	ENST00000559435.1	TSL:5	n.116A>G		non_coding_transcript_exon	Exon 2 of 6	ENSP00000457109.1

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 488 AN: 152224 Hom.: 2 Cov.: 32

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

GnomAD2 exomes AF: 0.000780 AC: 196 AN: 251434 AF XY: 0.000611

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 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

African (AFR) AF: 0.0111 AC: 371 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1112004

Other (OTH) AF: 0.000679 AC: 41 AN: 60394

GnomAD4 genome AF: 0.00323 AC: 492 AN: 152342 Hom.: 2 Cov.: 32 AF XY: 0.00309 AC XY: 230 AN XY: 74500

African (AFR) AF: 0.0113 AC: 471 AN: 41582

American (AMR) AF: 0.000784 AC: 12 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00108 Hom.: 5

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Colorectal cancer (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Mosaic variegated aneuploidy syndrome 1 (1)
-	-	1	Premature chromatid separation trait (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.90	N
PhyloP100		1.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.029
Sift	Benign	0.76	T
Sift4G	Benign	0.81	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
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs34998711; hg19: chr15-40512818;