X-50294948-C-T

Position:

• chrX-50294948-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_033031.3(CCNB3):​c.290C>T​(p.Thr97Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000907 in 1,207,764 control chromosomes in the GnomAD database, including 4 homozygotes. There are 359 hemizygotes in GnomAD. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00067 (1 hom., 22 hem., cov: 22)
  • Exomes 𝑓: 0.00093 (3 hom. 337 hem.)
• Consequence: CCNB3 NM_033031.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0460

Genes affected

CCNB3 (HGNC:18709): (cyclin B3) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as positive regulators of cyclin-dependent kinases (CDKs), and thereby play an essential role in the control of the cell cycle. Different cyclins exhibit distinct expression and degradation patterns, which contribute to the temporal coordination of each mitotic event. Studies of similar genes in chicken and drosophila suggest that this cyclin may associate with CDC2 and CDK2 kinases, and may be required for proper spindle reorganization and restoration of the interphase nucleus. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052047074).
• BS2: High Hemizygotes in GnomAd4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCNB3	NM_033031.3	c.290C>T	p.Thr97Ile	missense_variant	5/13	ENST00000376042.6	NP_149020.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCNB3	ENST00000376042.6	c.290C>T	p.Thr97Ile	missense_variant	5/13	2	NM_033031.3	ENSP00000365210	P1

Frequencies

GnomAD3 genomes AF: 0.000673 AC: 75 AN: 111362 Hom.: 1 Cov.: 22 AF XY: 0.000655 AC XY: 22 AN XY: 33584

Gnomad AFR AF: 0.0000980

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00719

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000383

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000885

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000962 AC: 176 AN: 182951 Hom.: 0 AF XY: 0.00105 AC XY: 71 AN XY: 67479

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000403

Gnomad ASJ exome AF: 0.00763

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000918

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000931 AC: 1021 AN: 1096351 Hom.: 3 Cov.: 29 AF XY: 0.000931 AC XY: 337 AN XY: 361843

Gnomad4 AFR exome AF: 0.000228

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00760

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00134

Gnomad4 FIN exome AF: 0.0000741

Gnomad4 NFE exome AF: 0.000825

Gnomad4 OTH exome AF: 0.00122

GnomAD4 genome AF: 0.000673 AC: 75 AN: 111413 Hom.: 1 Cov.: 22 AF XY: 0.000654 AC XY: 22 AN XY: 33645

Gnomad4 AFR AF: 0.0000978

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00719

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000385

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000885

Gnomad4 OTH AF: 0.00132

Alfa AF: 0.00132 Hom.: 54

Bravo AF: 0.000740

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00173 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00134 AC: 9

ExAC AF: 0.000881 AC: 107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.290C>T (p.T97I) alteration is located in exon 4 (coding exon 3) of the CCNB3 gene. This alteration results from a C to T substitution at nucleotide position 290, causing the threonine (T) at amino acid position 97 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.4
DANN	Uncertain	0.99
DEOGEN2	Benign	0.047	T;T
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.48	.;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.018	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.77	P;P
Vest4		0.075
MVP		0.20
MPC		0.18
ClinPred		0.0078	T
GERP RS		1.6
Varity_R		0.087
gMVP		0.15

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: rs151272775; hg19: chrX-50037948;