5-55128432-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001170402.1(CDC20B):c.883G>A(p.Gly295Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,450,998 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CDC20B NM_001170402.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73

Genes affected

CDC20B (HGNC:24222): (cell division cycle 20B) Predicted to enable anaphase-promoting complex binding activity and ubiquitin ligase activator activity. Predicted to be involved in anaphase-promoting complex-dependent catabolic process and positive regulation of anaphase-promoting complex-dependent catabolic process. Predicted to be part of anaphase-promoting complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDC20B	NM_001170402.1	c.883G>A	p.Gly295Arg	missense_variant	7/12	ENST00000381375.7
CDC20B	NM_152623.2	c.883G>A	p.Gly295Arg	missense_variant	7/12
CDC20B	NM_001145734.2	c.883G>A	p.Gly295Arg	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDC20B	ENST00000381375.7	c.883G>A	p.Gly295Arg	missense_variant	7/12	1	NM_001170402.1	A1
CDC20B	ENST00000296733.5	c.883G>A	p.Gly295Arg	missense_variant	7/12	1		P4
CDC20B	ENST00000322374.10	c.883G>A	p.Gly295Arg	missense_variant	7/11	1
CDC20B	ENST00000513180.5	c.883G>A	p.Gly295Arg	missense_variant, NMD_transcript_variant	7/12	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000125 AC: 3 AN: 239640 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129348

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000937

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450998 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721400

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000955

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 15, 2022

The c.883G>A (p.G295R) alteration is located in exon 7 (coding exon 7) of the CDC20B gene. This alteration results from a G to A substitution at nucleotide position 883, causing the glycine (G) at amino acid position 295 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	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	26
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	3.4	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.65
MutPred		0.63		Loss of catalytic residue at Q298 (P = 0.0536);Loss of catalytic residue at Q298 (P = 0.0536);Loss of catalytic residue at Q298 (P = 0.0536);
MVP		0.67
MPC		0.75
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.74
gMVP		0.68

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: rs1172613043; hg19: chr5-54424260;