Genetic Variant CDK3:p.Arg150His (chr17-76002381-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001258.4(CDK3):c.449G>A(p.Arg150His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,326 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: 0.0000014 ( 0 hom. )

Consequence

CDK3
NM_001258.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.94

Variant links:

Genes affected

CDK3 (HGNC:1772): (cyclin dependent kinase 3) This gene encodes a member of the cyclin-dependent protein kinase family. The protein promotes entry into S phase, in part by activating members of the E2F family of transcription factors. The protein also associates with cyclin C and phosphorylates the retinoblastoma 1 protein to promote exit from G0. [provided by RefSeq, Jul 2008]

CDK3 links:

TEN1-CDK3 (HGNC:44420): (TEN1-CDK3 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring TEN1 telomerase capping complex subunit homolog (S. cerevisiae) and cyclin-dependent kinase 3 (CDK3) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is therefore unlikely to produce a protein product. [provided by RefSeq, Oct 2011]

TEN1-CDK3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK3	NM_001258.4 link	c.449G>A	p.Arg150His	missense_variant	Exon 5 of 8	ENST00000448471.3	NP_001249.1	Q00526
TEN1-CDK3	NR_037709.1 link	n.2285G>A		non_coding_transcript_exon_variant	Exon 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDK3	ENST00000448471.3 link	c.449G>A	p.Arg150His	missense_variant	Exon 5 of 8	5	NM_001258.4	ENSP00000400088.1	Q00526
TEN1-CDK3	ENST00000649294.1 link	n.*590G>A		non_coding_transcript_exon_variant	Exon 8 of 11			ENSP00000497034.1
TEN1-CDK3	ENST00000649294.1 link	n.*590G>A		3_prime_UTR_variant	Exon 8 of 11			ENSP00000497034.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250014

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135208

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

0.00000137

AC:

AN:

1460326

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726460

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.449G>A (p.R150H) alteration is located in exon 5 (coding exon 4) of the CDK3 gene. This alteration results from a G to A substitution at nucleotide position 449, causing the arginine (R) at amino acid position 150 to be replaced by a histidine (H). 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

0.97

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;T;T;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;.;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.4

.;M;M;.

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.8

.;D;D;.

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

.;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.90

MutPred

0.85

Loss of methylation at R150 (P = 0.0192);Loss of methylation at R150 (P = 0.0192);Loss of methylation at R150 (P = 0.0192);.;

MVP

0.68

MPC

1.4

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.58

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