14-50345053-G-A

Variant names:

• chr14-50345053-G-A
• NM_004196.7:c.296C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004196.7(CDKL1):​c.296C>T​(p.Pro99Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKL1 NM_004196.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27

Genes affected

CDKL1 (HGNC:1781): (cyclin dependent kinase like 1) This gene product is a member of a large family of CDC2-related serine/threonine protein kinases that accumulates primarily in the nucleus. [provided by RefSeq, Nov 2018]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL1	NM_004196.7	c.296C>T	p.Pro99Leu	missense_variant	Exon 4 of 10	ENST00000395834.6	NP_004187.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL1	ENST00000395834.6	c.296C>T	p.Pro99Leu	missense_variant	Exon 4 of 10	1	NM_004196.7	ENSP00000379176.2
CDKL1	ENST00000216378.2	c.299C>T	p.Pro100Leu	missense_variant	Exon 4 of 9	1		ENSP00000216378.2
CDKL1	ENST00000356146.5	n.2227-1995C>T		intron_variant	Intron 15 of 19	1
CDKL1	ENST00000528197.5	n.354C>T		non_coding_transcript_exon_variant	Exon 4 of 6	4

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

Feb 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.299C>T (p.P100L) alteration is located in exon 3 (coding exon 3) of the CDKL1 gene. This alteration results from a C to T substitution at nucleotide position 299, causing the proline (P) at amino acid position 100 to be replaced by a leucine (L). 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	0.44
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.78	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.022	D;T
Sift4G	Benign	0.10	T;T
Vest4		0.80
MVP		0.28
MPC		0.58
ClinPred		0.96	D
GERP RS		5.5
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-50811771;