4-75597003-A-T

Position:

• chr4-75597003-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330724.2(CDKL2):​c.1254T>A​(p.Asn418Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDKL2 NM_001330724.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0360

Genes affected

CDKL2 (HGNC:1782): (cyclin dependent kinase like 2) This gene product is a member of a large family of CDC2-related serine/threonine protein kinases. It accumulates primarily in the cytoplasm, with lower levels in the nucleus. [provided by RefSeq, Jul 2008]

CDKL2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26332814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL2	NM_001330724.2	c.1254T>A	p.Asn418Lys	missense_variant	9/14	ENST00000307465.9	NP_001317653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL2	ENST00000307465.9	c.1254T>A	p.Asn418Lys	missense_variant	9/14	2	NM_001330724.2	ENSP00000306340.4
CDKL2	ENST00000429927.6	c.1254T>A	p.Asn418Lys	missense_variant	9/12	1		ENSP00000412365.2
CDKL2	ENST00000515793.1	n.138T>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2024

The c.1254T>A (p.N418K) alteration is located in exon 9 (coding exon 8) of the CDKL2 gene. This alteration results from a T to A substitution at nucleotide position 1254, causing the asparagine (N) at amino acid position 418 to be replaced by a lysine (K). 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	Benign	0.13
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.093
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.95	P;.
Vest4		0.52
MutPred		0.37		Gain of ubiquitination at N418 (P = 0.0128);Gain of ubiquitination at N418 (P = 0.0128);
MVP		0.65
MPC		0.031
ClinPred		0.57	D
GERP RS		-4.0
Varity_R		0.17
gMVP		0.35

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

Other links and lift over

dbSNP: rs373031282; hg19: chr4-76522187;