chr4-75605594-T-A

Position:

• chr4-75605594-T-A

Variant summary

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

The NM_001330724.2(CDKL2):​c.583A>T​(p.Met195Leu) variant causes a missense change. 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: CDKL2 NM_001330724.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.24

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL2	NM_001330724.2	c.583A>T	p.Met195Leu	missense_variant	5/14	ENST00000307465.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL2	ENST00000307465.9	c.583A>T	p.Met195Leu	missense_variant	5/14	2	NM_001330724.2	P1
CDKL2	ENST00000429927.6	c.583A>T	p.Met195Leu	missense_variant	5/12	1
CDKL2	ENST00000506234.1	c.169-1638A>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jan 29, 2024

The c.583A>T (p.M195L) alteration is located in exon 5 (coding exon 4) of the CDKL2 gene. This alteration results from a A to T substitution at nucleotide position 583, causing the methionine (M) at amino acid position 195 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	Benign	0.31
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0096	T
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.89	N;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.22
Sift	Benign	0.42	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.93	P;.
Vest4		0.83
MutPred		0.56		Loss of disorder (P = 0.2573);Loss of disorder (P = 0.2573);
MVP		0.40
MPC		0.030
ClinPred		0.58	D
GERP RS		4.2
Varity_R		0.42
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1206467376; hg19: chr4-76530778;