Genetic Variant CDK18:p.Arg112Thr (chr1-205523687-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_212503.3(CDK18):c.335G>C(p.Arg112Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000886 in 1,353,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 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: 0.0000089 ( 0 hom. )

Consequence

CDK18
NM_212503.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.668

Variant links:

Genes affected

CDK18 (HGNC:8751): (cyclin dependent kinase 18) Predicted to enable ATP binding activity; cyclin-dependent protein serine/threonine kinase activity; and protein serine kinase activity. Predicted to be involved in protein phosphorylation and regulation of transcription involved in G1/S transition of mitotic cell cycle. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CDK18 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07751706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK18	NM_212502.3 link	c.273+62G>C		intron_variant	Intron 3 of 15	ENST00000429964.7	NP_997667.1	Q07002-2A0A024R996Q59G02

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK18	ENST00000429964.7 link	c.273+62G>C		intron_variant	Intron 3 of 15	1	NM_212502.3	ENSP00000399082.2		Q07002-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

125358

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65626

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000400

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000886

AC:

AN:

1353766

Hom.:

Cov.:

AF XY:

0.00000755

AC XY:

AN XY:

662310

show subpopulations

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:

0.0000114

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000764

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.335G>C (p.R112T) alteration is located in exon 3 (coding exon 2) of the CDK18 gene. This alteration results from a G to C substitution at nucleotide position 335, causing the arginine (R) at amino acid position 112 to be replaced by a threonine (T). 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

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.32

CADD

Benign

6.0

DANN

Benign

0.74

DEOGEN2

Benign

0.031

.;T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.50

T;T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.078

T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.73

N;N;N;N

REVEL

Benign

0.068

Sift

Benign

0.060

T;T;T;D

Sift4G

Benign

0.24

T;T;T;T

Polyphen

0.0030

B;.;.;.

Vest4

0.31

MutPred

0.40

Loss of MoRF binding (P = 0.0131);.;.;Loss of MoRF binding (P = 0.0131);

MVP

0.32

MPC

0.31

ClinPred

0.45

GERP RS

-0.20

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over