rs34999621

Variant names:

• chr15-40212636-C-T
• rs34999621
• NM_001211.6:c.2523C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001211.6(BUB1B):​c.2523C>T​(p.Cys841Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,613,216 control chromosomes in the GnomAD database, including 237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (114 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (123 hom.)
• Consequence: BUB1B NM_001211.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.453
• Publications: 2 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 15-40212636-C-T is Benign according to our data. Variant chr15-40212636-C-T is described in ClinVar as Benign. ClinVar VariationId is 257636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.453 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

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.2523C>T	p.Cys841Cys	synonymous	Exon 19 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.2523C>T	p.Cys841Cys	synonymous	Exon 19 of 23	ENSP00000287598.7
	BUB1B	ENST00000412359.7	TSL:2	c.2565C>T	p.Cys855Cys	synonymous	Exon 19 of 23	ENSP00000398470.3
	BUB1B	ENST00000918306.1		c.2625C>T	p.Cys875Cys	synonymous	Exon 20 of 24	ENSP00000588365.1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3366 AN: 152132 Hom.: 114 Cov.: 33

Gnomad AFR AF: 0.0777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00548 AC: 1376 AN: 251048 AF XY: 0.00432

Gnomad AFR exome AF: 0.0773

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00213 AC: 3113 AN: 1460966 Hom.: 123 Cov.: 31 AF XY: 0.00179 AC XY: 1298 AN XY: 726848

African (AFR) AF: 0.0779 AC: 2604 AN: 33418

American (AMR) AF: 0.00349 AC: 156 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.000901 AC: 5 AN: 5548

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111702

Other (OTH) AF: 0.00462 AC: 279 AN: 60356

GnomAD4 genome AF: 0.0222 AC: 3375 AN: 152250 Hom.: 114 Cov.: 33 AF XY: 0.0214 AC XY: 1594 AN XY: 74436

African (AFR) AF: 0.0777 AC: 3225 AN: 41520

American (AMR) AF: 0.00706 AC: 108 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68026

Other (OTH) AF: 0.0156 AC: 33 AN: 2112

Alfa AF: 0.0110 Hom.: 56

Bravo AF: 0.0250

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Colorectal cancer (1)
-	-	1	Mosaic variegated aneuploidy syndrome 1 (1)
-	-	1	not specified (1)
-	-	1	Premature chromatid separation trait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.0
DANN	Benign	0.72
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs34999621; hg19: chr15-40504837; COSMIC: COSV104598977;