4-75597050-C-G

Position:

• chr4-75597050-C-G

Variant summary

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

The NM_001330724.2(CDKL2):​c.1207G>C​(p.Asp403His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CDKL2 NM_001330724.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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=0.17436948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL2	NM_001330724.2	c.1207G>C	p.Asp403His	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.1207G>C	p.Asp403His	missense_variant	9/14	2	NM_001330724.2	ENSP00000306340.4
CDKL2	ENST00000429927.6	c.1207G>C	p.Asp403His	missense_variant	9/12	1		ENSP00000412365.2
CDKL2	ENST00000515793.1	n.91G>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Aug 12, 2024

The c.1207G>C (p.D403H) alteration is located in exon 9 (coding exon 8) of the CDKL2 gene. This alteration results from a G to C substitution at nucleotide position 1207, causing the aspartic acid (D) at amino acid position 403 to be replaced by a histidine (H). 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	0.11
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.12
Sift	Benign	0.055	T;D
Sift4G	Benign	0.067	T;T
Polyphen		0.012	B;.
Vest4		0.30
MutPred		0.14		Gain of glycosylation at T405 (P = 0.0918);Gain of glycosylation at T405 (P = 0.0918);
MVP		0.74
MPC		0.020
ClinPred		0.14	T
GERP RS		3.3
Varity_R		0.091
gMVP		0.29

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: rs1342916491; hg19: chr4-76522234;