Genetic Variant NM_001287135.2:c.433T>A (chr7-90747744-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001287135.2(CDK14):c.433T>A(p.Ser145Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,436 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CDK14
NM_001287135.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.66

Publications

0 publications found

Variant links:

Genes affected

CDK14 (HGNC:8883): (cyclin dependent kinase 14) Enables cyclin binding activity and cyclin-dependent protein serine/threonine kinase activity. Involved in G2/M transition of mitotic cell cycle and regulation of canonical Wnt signaling pathway. Located in cytosol; nucleoplasm; and plasma membrane. Part of cytoplasmic cyclin-dependent protein kinase holoenzyme complex. [provided by Alliance of Genome Resources, Apr 2022]

CDK14 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK14	NM_001287135.2 link	c.433T>A	p.Ser145Thr	missense_variant	Exon 4 of 15	ENST00000380050.8	NP_001274064.1	O94921-1
CDK14	NM_012395.3 link	c.379T>A	p.Ser127Thr	missense_variant	Exon 3 of 14		NP_036527.1	O94921-2
CDK14	NM_001287136.1 link	c.295T>A	p.Ser99Thr	missense_variant	Exon 3 of 14		NP_001274065.1	O94921-3
CDK14	NM_001287137.1 link	c.77+20932T>A		intron_variant	Intron 2 of 12		NP_001274066.1	O94921E7EUK8B4DK59

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK14	ENST00000380050.8 link	c.433T>A	p.Ser145Thr	missense_variant	Exon 4 of 15	1	NM_001287135.2	ENSP00000369390.3		O94921-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1444436

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

718130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32378

American (AMR)

AF:

0.00

AC:

AN:

40402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25856

East Asian (EAS)

AF:

0.00

AC:

AN:

38736

South Asian (SAS)

AF:

0.0000244

AC:

AN:

81928

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106394

Other (OTH)

AF:

0.00

AC:

AN:

59732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.379T>A (p.S127T) alteration is located in exon 3 (coding exon 3) of the CDK14 gene. This alteration results from a T to A substitution at nucleotide position 379, causing the serine (S) at amino acid position 127 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

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.027

T;T;T;T;T;.;.

Eigen

Benign

0.038

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.43

.;.;.;T;T;T;T

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.59

D;D;D;D;D;D;D

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.12

.;.;.;.;N;.;.

PhyloP100

7.7

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.28

N;N;N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.73

T;T;T;T;T;T;T

Sift4G

Benign

0.95

T;T;T;T;T;T;T

Polyphen

0.96, 0.32

.;.;.;.;D;B;.

Vest4

0.66, 0.79, 0.78

MutPred

0.80

.;.;.;.;Loss of phosphorylation at S145 (P = 0.0541);.;.;

MVP

0.67

MPC

0.33

ClinPred

0.77

GERP RS

5.9

Varity_R

0.23

gMVP

0.54

Mutation Taster

=24/76

disease causing

(source)

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

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NM_001287135.2:c.433T>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over