ENST00000406263.5:c.2T>C

Variant names:

• chr7-90726583-T-C
• ENST00000406263.5:c.2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The ENST00000406263.5(CDK14):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK14 ENST00000406263.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 9 codons. Genomic position: 90726606. Lost 0.020 part of the original CDS.
• 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	c.140T>C	p.Met47Thr	missense_variant	Exon 3 of 15	ENST00000380050.8	NP_001274064.1
CDK14	NM_001287136.1	c.2T>C	p.Met1?	start_lost	Exon 2 of 14		NP_001274065.1
CDK14	NM_012395.3	c.86T>C	p.Met29Thr	missense_variant	Exon 2 of 14		NP_036527.1
CDK14	NM_001287137.1	c.-153T>C		5_prime_UTR_variant	Exon 2 of 13		NP_001274066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK14	ENST00000380050.8	c.140T>C	p.Met47Thr	missense_variant	Exon 3 of 15	1	NM_001287135.2	ENSP00000369390.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.86T>C (p.M29T) alteration is located in exon 2 (coding exon 2) of the CDK14 gene. This alteration results from a T to C substitution at nucleotide position 86, causing the methionine (M) at amino acid position 29 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	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	23
DANN	Benign	0.91
DEOGEN2	Benign	0.063	T;T;T;T;T;T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	.;.;.;D;D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.60	D;D;D;D;T;D;T;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.69	.;.;.;.;N;.;.;.
PhyloP100		7.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.3	N;N;N;N;N;D;N;N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D;D;D;T;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;T;D;D;D
Polyphen		0.72, 0.81	.;.;.;.;P;.;P;.
Vest4		0.88, 0.79, 0.88
MutPred		0.16		.;.;.;.;Gain of phosphorylation at M47 (P = 0.0471);.;.;.;
MVP		0.83
MPC		0.67
ClinPred		0.66	D
GERP RS		5.7
Varity_R		0.37
gMVP		0.46
Mutation Taster		=26/174	disease causing

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

Other links and lift over

hg19: chr7-90355897;