rs12623473

Variant names:

• chr2-110660580-T-C
• rs12623473
• NM_004336.5:c.1218-544A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004336.5(BUB1):​c.1218-544A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00809 in 152,260 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0081 (75 hom., cov: 32)
• Consequence: BUB1 NM_004336.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.105
• Publications: 2 publications found

Genes affected

BUB1 (HGNC:1148): (BUB1 mitotic checkpoint serine/threonine kinase) This gene encodes a serine/threonine-protein kinase that play a central role in mitosis. The encoded protein functions in part by phosphorylating members of the mitotic checkpoint complex and activating the spindle checkpoint. This protein also plays a role in inhibiting the activation of the anaphase promoting complex/cyclosome. This protein may also function in the DNA damage response. Mutations in this gene have been associated with aneuploidy and several forms of cancer. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

BUB1 Gene-Disease associations (from GenCC):

• microcephaly 30, primary, autosomal recessive

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• mosaic variegated aneuploidy syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen, Ambry Genetics
• familial colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000289202 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004336.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1	NM_004336.5	MANE Select	c.1218-544A>G		intron	N/A	NP_004327.1	O43683-1
	BUB1	NM_001278616.2		c.1158-544A>G		intron	N/A	NP_001265545.1	O43683-3
	BUB1	NM_001278617.2		c.1218-544A>G		intron	N/A	NP_001265546.1	O43683-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1	ENST00000302759.11	TSL:1 MANE Select	c.1218-544A>G		intron	N/A	ENSP00000302530.6	O43683-1
	BUB1	ENST00000409311.5	TSL:1	c.1218-544A>G		intron	N/A	ENSP00000386701.1	O43683-2
	BUB1	ENST00000466333.5	TSL:1	n.1251-544A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1237 AN: 152142 Hom.: 77 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.00613

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00956

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00809 AC: 1232 AN: 152260 Hom.: 75 Cov.: 32 AF XY: 0.00985 AC XY: 733 AN XY: 74446

African (AFR) AF: 0.000144 AC: 6 AN: 41562

American (AMR) AF: 0.00118 AC: 18 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.168 AC: 871 AN: 5174

South Asian (SAS) AF: 0.0340 AC: 164 AN: 4818

European-Finnish (FIN) AF: 0.00613 AC: 65 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68022

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00485 Hom.: 19

Bravo AF: 0.00808

Asia WGS AF: 0.0880 AC: 306 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.2
DANN	Benign	0.73
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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: rs12623473; hg19: chr2-111418157;