4-75603935-T-G

Position:

• chr4-75603935-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001330724.2(CDKL2):​c.677A>C​(p.Gln226Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 6.74

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL2	NM_001330724.2	c.677A>C	p.Gln226Pro	missense_variant	6/14	ENST00000307465.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL2	ENST00000307465.9	c.677A>C	p.Gln226Pro	missense_variant	6/14	2	NM_001330724.2	P1
CDKL2	ENST00000429927.6	c.677A>C	p.Gln226Pro	missense_variant	6/12	1
CDKL2	ENST00000506234.1	c.*13A>C		3_prime_UTR_variant, NMD_transcript_variant	3/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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 25, 2023

The c.677A>C (p.Q226P) alteration is located in exon 6 (coding exon 5) of the CDKL2 gene. This alteration results from a A to C substitution at nucleotide position 677, causing the glutamine (Q) at amino acid position 226 to be replaced by a proline (P). 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	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.71	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.041	D;D
Polyphen		0.82	P;.
Vest4		0.85
MutPred		0.69		Gain of methylation at K231 (P = 0.1376);Gain of methylation at K231 (P = 0.1376);
MVP		0.67
MPC		0.047
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.95
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-76529119;