2-110658451-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/21 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

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BUB1	NM_004336.5	c.1475C>A	p.Ser492Tyr	missense_variant	Exon 13 of 25	ENST00000302759.11	NP_004327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BUB1	ENST00000302759.11	c.1475C>A	p.Ser492Tyr	missense_variant	Exon 13 of 25	1	NM_004336.5	ENSP00000302530.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Colorectal cancer with chromosomal instability, somatic Pathogenic:1

Mar 19, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	.;M;M
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.99	.;.;D
Vest4		0.47
MutPred		0.34		.;Loss of disorder (P = 0.0069);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909055; hg19: chr2-111416028;