15-59114475-T-C

Position:

• chr15-59114475-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004701.4(CCNB2):​c.299T>C​(p.Met100Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,611,988 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0047 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (3 hom.)
• Consequence: CCNB2 NM_004701.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.09

Genes affected

CCNB2 (HGNC:1580): (cyclin B2) Cyclin B2 is a member of the cyclin family, specifically the B-type cyclins. The B-type cyclins, B1 and B2, associate with p34cdc2 and are essential components of the cell cycle regulatory machinery. B1 and B2 differ in their subcellular localization. Cyclin B1 co-localizes with microtubules, whereas cyclin B2 is primarily associated with the Golgi region. Cyclin B2 also binds to transforming growth factor beta RII and thus cyclin B2/cdc2 may play a key role in transforming growth factor beta-mediated cell cycle control. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059137642).
• BP6: Variant 15-59114475-T-C is Benign according to our data. Variant chr15-59114475-T-C is described in ClinVar as [Benign]. Clinvar id is 711953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00465 (709/152340) while in subpopulation AFR AF= 0.0163 (677/41570). AF 95% confidence interval is 0.0153. There are 6 homozygotes in gnomad4. There are 335 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCNB2	NM_004701.4	c.299T>C	p.Met100Thr	missense_variant	4/9	ENST00000288207.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCNB2	ENST00000288207.7	c.299T>C	p.Met100Thr	missense_variant	4/9	1	NM_004701.4	P1
CCNB2	ENST00000621385.1	c.299T>C	p.Met100Thr	missense_variant	4/8	1
CCNB2	ENST00000559622.5	c.56T>C	p.Met19Thr	missense_variant	2/6	5
CCNB2	ENST00000561077.1	n.548T>C		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.00464 AC: 706 AN: 152222 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

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: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00111 AC: 276 AN: 249206 Hom.: 1 AF XY: 0.000712 AC XY: 96 AN XY: 134760

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.000821

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000466 AC: 680 AN: 1459648 Hom.: 3 Cov.: 32 AF XY: 0.000401 AC XY: 291 AN XY: 726124

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.000903

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00465 AC: 709 AN: 152340 Hom.: 6 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74504

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000984 Hom.: 3

Bravo AF: 0.00537

ESP6500AA AF: 0.0164 AC: 72

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00142 AC: 172

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Benign	0.085
Sift	Benign	0.65	T;T;.
Sift4G	Benign	0.59	T;T;T
Polyphen		0.040	B;.;.
Vest4		0.38
MVP		0.45
MPC		0.33
ClinPred		0.021	T
GERP RS		4.2
Varity_R		0.090
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs16941036; hg19: chr15-59406674;