2-110638019-G-A

Position:

• chr2-110638019-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004336.5(BUB1):​c.3203C>T​(p.Ala1068Val) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BUB1 NM_004336.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16682646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BUB1	NM_004336.5	c.3203C>T	p.Ala1068Val	missense_variant	25/25	ENST00000302759.11	NP_004327.1
BUB1	NM_001278616.2	c.3143C>T	p.Ala1048Val	missense_variant	24/24		NP_001265545.1
BUB1	NM_001278617.2	c.3032C>T	p.Ala1011Val	missense_variant	24/24		NP_001265546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BUB1	ENST00000302759.11	c.3203C>T	p.Ala1068Val	missense_variant	25/25	1	NM_004336.5	ENSP00000302530	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The p.A1068V variant (also known as c.3203C>T), located in coding exon 25 of the BUB1 gene, results from a C to T substitution at nucleotide position 3203. The alanine at codon 1068 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	.;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.074
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.044
Sift	Benign	0.075	T;D;T
Sift4G	Benign	0.065	T;T;T
Polyphen		0.010	.;.;B
Vest4		0.035
MutPred		0.44		.;.;Gain of sheet (P = 0.0507);
MVP		0.63
MPC		0.13
ClinPred		0.28	T
GERP RS		5.9
Varity_R		0.073
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-111395596;