rs121909055

Variant names:

• chr2-110658451-G-T
• rs121909055
• NM_004336.5:c.1475C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-110658451-G-T
• chr2-110658451-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_004336.5(BUB1):​c.1475C>A​(p.Ser492Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BUB1 NM_004336.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.944
• Publications: 4 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]

ENSG00000289202 (HGNC:):

SNORD132 (HGNC:50413): (small nucleolar RNA, C/D box 132)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-110658451-G-T is Pathogenic according to our data. Variant chr2-110658451-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7083.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38702524). . Strength limited to SUPPORTING due to the PP5.

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.1475C>A	p.Ser492Tyr	missense	Exon 13 of 25	NP_004327.1	O43683-1
	BUB1	NM_001278616.2		c.1415C>A	p.Ser472Tyr	missense	Exon 12 of 24	NP_001265545.1	O43683-3
	BUB1	NM_001278617.2		c.1475C>A	p.Ser492Tyr	missense	Exon 13 of 24	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.1475C>A	p.Ser492Tyr	missense	Exon 13 of 25	ENSP00000302530.6	O43683-1
	BUB1	ENST00000409311.5	TSL:1	c.1475C>A	p.Ser492Tyr	missense	Exon 13 of 24	ENSP00000386701.1	O43683-2
	BUB1	ENST00000466333.5	TSL:1	n.1508C>A		non_coding_transcript_exon	Exon 13 of 20

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Colorectal cancer with chromosomal instability, somatic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.94
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.47
MutPred		0.34		Loss of disorder (P = 0.0069)
MVP		0.77
MPC		0.61
ClinPred		0.84	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.33
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs121909055; hg19: chr2-111416028;