5-134308226-C-T

Variant names:

• chr5-134308226-C-T
• rs1481428018
• NM_001113575.2:c.1276G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001113575.2(CDKL3):​c.1276G>A​(p.Gly426Ser) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKL3 NM_001113575.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.375

Genes affected

CDKL3 (HGNC:15483): (cyclin dependent kinase like 3) The protein encoded by this gene is a member of cyclin-dependent protein kinase (CDK) family. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression. This gene was identified as a gene absent in leukemic patients with chromosome 5q deletion. This loss may be an important determinant of dysmyelopoiesis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ENSG00000273345 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0484187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL3	NM_001113575.2	c.1276G>A	p.Gly426Ser	missense_variant	Exon 9 of 13	ENST00000265334.9	NP_001107047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL3	ENST00000265334.9	c.1276G>A	p.Gly426Ser	missense_variant	Exon 9 of 13	1	NM_001113575.2	ENSP00000265334.4
ENSG00000273345	ENST00000703317.1	n.86-5539G>A		intron_variant	Intron 2 of 9			ENSP00000515260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

May 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1276G>A (p.G426S) alteration is located in exon 9 (coding exon 8) of the CDKL3 gene. This alteration results from a G to A substitution at nucleotide position 1276, causing the glycine (G) at amino acid position 426 to be replaced by a serine (S). 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	0.063
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	4.5
DANN	Benign	0.36
DEOGEN2	Benign	0.0088	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.64	T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.048	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.94	L;.;.;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.20	N;N;N;N
REVEL	Benign	0.072
Sift	Benign	0.37	T;T;T;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.0060	B;B;.;.
Vest4		0.16
MutPred		0.10		Gain of glycosylation at T429 (P = 0.0938);.;Gain of glycosylation at T429 (P = 0.0938);Gain of glycosylation at T429 (P = 0.0938);
MVP		0.29
MPC		0.020
ClinPred		0.28	T
GERP RS		1.1
Varity_R		0.028
gMVP		0.071

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1481428018; hg19: chr5-133643917;