NM_001211.6:c.1066T>C

Variant names:

• chr15-40196552-T-C
• rs370655726
• NM_001211.6:c.1066T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_001211.6(BUB1B):​c.1066T>C​(p.Cys356Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. C356Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 6.18
• Publications: 3 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-40196553-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2445378.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

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.1066T>C	p.Cys356Arg	missense	Exon 9 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.1066T>C	p.Cys356Arg	missense	Exon 9 of 23	ENSP00000287598.7	O60566-1
	BUB1B	ENST00000412359.7	TSL:2	c.1108T>C	p.Cys370Arg	missense	Exon 9 of 23	ENSP00000398470.3	O60566-3
	BUB1B	ENST00000918306.1		c.1168T>C	p.Cys390Arg	missense	Exon 10 of 24	ENSP00000588365.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461180 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726878

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111480

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.39
Sift	Benign	0.086	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.73
MutPred		0.56		Gain of MoRF binding (P = 0.0105)
MVP		0.64
MPC		1.0
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.70
gMVP		0.47
Mutation Taster		=55/45	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: rs370655726; hg19: chr15-40488753;