X-50288799-C-G

Position:

• chrX-50288799-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033031.3(CCNB3):​c.116C>G​(p.Thr39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,091,794 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: CCNB3 NM_033031.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.957

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03369972).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCNB3	NM_033031.3	c.116C>G	p.Thr39Arg	missense_variant	4/13	ENST00000376042.6	NP_149020.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCNB3	ENST00000376042.6	c.116C>G	p.Thr39Arg	missense_variant	4/13	2	NM_033031.3	ENSP00000365210.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1091794 Hom.: 0 Cov.: 27 AF XY: 0.00000280 AC XY: 1 AN XY: 357586

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000359

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

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

Dec 20, 2023

The c.116C>G (p.T39R) alteration is located in exon 3 (coding exon 2) of the CCNB3 gene. This alteration results from a C to G substitution at nucleotide position 116, causing the threonine (T) at amino acid position 39 to be replaced by an arginine (R). 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	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.035
DANN	Benign	0.56
DEOGEN2	Benign	0.025	T;.;T;.
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.35	.;.;T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.034	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.0	L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.80	N;N;N;N
REVEL	Benign	0.0080
Sift	Uncertain	0.0070	D;T;D;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.14
MutPred		0.28		Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);
MVP		0.082
MPC		0.19
ClinPred		0.043	T
GERP RS		-0.67
Varity_R		0.15
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-50031799;