10-12210292-G-T

Position:

• chr10-12210292-G-T

Variant summary

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

The NM_006023.3(CDC123):​c.207G>T​(p.Trp69Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDC123 NM_006023.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.34

Genes affected

CDC123 (HGNC:16827): (cell division cycle 123) Predicted to be involved in eukaryotic translation initiation factor 2 complex assembly and positive regulation of translational initiation. Located in cytoplasm. [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, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC123	NM_006023.3	c.207G>T	p.Trp69Cys	missense_variant, splice_region_variant	4/13	ENST00000281141.9	NP_006014.2
CDC123	XM_005252638.5	c.207G>T	p.Trp69Cys	missense_variant, splice_region_variant	4/12		XP_005252695.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC123	ENST00000281141.9	c.207G>T	p.Trp69Cys	missense_variant, splice_region_variant	4/13	1	NM_006023.3	ENSP00000281141.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 21, 2024

The c.207G>T (p.W69C) alteration is located in exon 4 (coding exon 4) of the CDC123 gene. This alteration results from a G to T substitution at nucleotide position 207, causing the tryptophan (W) at amino acid position 69 to be replaced by a cysteine (C). 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	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Pathogenic	3.1	.;M;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.3	D;D;D;D
REVEL	Uncertain	0.49
Sift	Benign	0.030	D;D;D;D
Sift4G	Benign	0.17	T;D;T;T
Polyphen		1.0	.;D;.;.
Vest4		0.73, 0.73
MutPred		0.50		Loss of phosphorylation at S70 (P = 0.1663);Loss of phosphorylation at S70 (P = 0.1663);Loss of phosphorylation at S70 (P = 0.1663);Loss of phosphorylation at S70 (P = 0.1663);
MVP		0.52
MPC		1.5
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.70
gMVP		0.57

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: chr10-12252291;