chr15-40161246-G-C

Variant names:

• chr15-40161246-G-C
• rs768279736
• NM_001211.6:c.26G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001211.6(BUB1B):​c.26G>C​(p.Gly9Ala) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.176
• Publications: 8 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 Gene-Disease associations (from GenCC):

• mosaic variegated aneuploidy syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• mosaic variegated aneuploidy syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084172726).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1B	NM_001211.6	MANE Select	c.26G>C	p.Gly9Ala	missense	Exon 1 of 23	NP_001202.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1B	ENST00000287598.11	TSL:1 MANE Select	c.26G>C	p.Gly9Ala	missense	Exon 1 of 23	ENSP00000287598.7	O60566-1
	BUB1B	ENST00000412359.7	TSL:2	c.26G>C	p.Gly9Ala	missense	Exon 1 of 23	ENSP00000398470.3	O60566-3
	BUB1B	ENST00000918306.1		c.26G>C	p.Gly9Ala	missense	Exon 1 of 24	ENSP00000588365.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246332 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Mosaic variegated aneuploidy syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	3.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.18
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.060
Sift	Benign	0.12	T
Sift4G	Benign	0.078	T
Polyphen		0.018	B
Vest4		0.086
MutPred		0.11		Loss of loop (P = 0.0073)
MVP		0.59
MPC		0.21
ClinPred		0.035	T
GERP RS		-0.59
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.1
Varity_R		0.036
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs768279736; hg19: chr15-40453447;