15-40212567-T-G

Variant names:

• chr15-40212567-T-G
• rs749203600
• NM_001211.6:c.2454T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001211.6(BUB1B):​c.2454T>G​(p.Asp818Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D818G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.975
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• rhabdomyosarcoma

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC107984763 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03726819).
• BP6: Variant 15-40212567-T-G is Benign according to our data. Variant chr15-40212567-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1791535.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1B	NM_001211.6	MANE Select	c.2454T>G	p.Asp818Glu	missense	Exon 19 of 23	NP_001202.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1B	ENST00000287598.11	TSL:1 MANE Select	c.2454T>G	p.Asp818Glu	missense	Exon 19 of 23	ENSP00000287598.7
	BUB1B	ENST00000412359.7	TSL:2	c.2496T>G	p.Asp832Glu	missense	Exon 19 of 23	ENSP00000398470.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460864 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726826

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111242

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Sep 01, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.0020
DANN	Benign	0.50
DEOGEN2	Benign	0.063	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.24	N
PhyloP100		-0.97
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.023
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.043
MutPred		0.43		Loss of stability (P = 0.1059)
MVP		0.64
MPC		0.18
ClinPred		0.023	T
GERP RS		-9.8
Varity_R		0.025
gMVP		0.072
Mutation Taster		=90/10	polymorphism

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: rs749203600; hg19: chr15-40504768;