17-76002252-A-G

Position:

chr17-76002252-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001258.4(CDK3):c.320A>G(p.Tyr107Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,611,542 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CDK3
NM_001258.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.43

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK3	NM_001258.4 link	c.320A>G	p.Tyr107Cys	missense_variant	5/8	ENST00000448471.3	NP_001249.1	Q00526
TEN1-CDK3	NR_037709.1 link	n.2156A>G		non_coding_transcript_exon_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CDK3	ENST00000448471.3 link	c.320A>G	p.Tyr107Cys	missense_variant	5/8	5	NM_001258.4	ENSP00000400088.1	Q00526
TEN1-CDK3	ENST00000649294.1 link	n.*461A>G		non_coding_transcript_exon_variant	8/11			ENSP00000497034.1
TEN1-CDK3	ENST00000649294.1 link	n.*461A>G		3_prime_UTR_variant	8/11			ENSP00000497034.1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249318

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134800

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1459910

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726310

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:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151632

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74028

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2023

The c.320A>G (p.Y107C) alteration is located in exon 5 (coding exon 4) of the CDK3 gene. This alteration results from a A to G substitution at nucleotide position 320, causing the tyrosine (Y) at amino acid position 107 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

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T;T;.

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.97

D;D;.;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.7

.;L;L;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.7

.;D;D;.

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

.;D;D;.

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

0.98

.;D;D;.

Vest4

0.89

MutPred

0.70

Gain of catalytic residue at L108 (P = 0.0103);Gain of catalytic residue at L108 (P = 0.0103);Gain of catalytic residue at L108 (P = 0.0103);.;

MVP

0.56

MPC

1.4

ClinPred

1.0

GERP RS

5.2

Varity_R

0.84

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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