10-12249677-A-G

Position:

• chr10-12249677-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006023.3(CDC123):​c.943A>G​(p.Thr315Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CDC123 NM_006023.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.53

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3376064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDC123	NM_006023.3	c.943A>G	p.Thr315Ala	missense_variant	12/13	ENST00000281141.9	NP_006014.2
CDC123	XM_005252638.5	c.847A>G	p.Thr283Ala	missense_variant	11/12		XP_005252695.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDC123	ENST00000281141.9	c.943A>G	p.Thr315Ala	missense_variant	12/13	1	NM_006023.3	ENSP00000281141.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461810 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727208

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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 02, 2024

The c.943A>G (p.T315A) alteration is located in exon 12 (coding exon 12) of the CDC123 gene. This alteration results from a A to G substitution at nucleotide position 943, causing the threonine (T) at amino acid position 315 to be replaced by an alanine (A). 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	0.078
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.12
Sift	Benign	0.091	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.13	B;.
Vest4		0.43
MutPred		0.45		Loss of phosphorylation at T315 (P = 0.0579);.;
MVP		0.55
MPC		0.39
ClinPred		0.53	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.54

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: rs937991849; hg19: chr10-12291676;