ENST00000395035.4:c.368T>G

Variant names:

• chr2-39204613-A-C
• rs1677055215
• ENST00000395035.4:c.368T>G

Variant summary

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

The ENST00000395035.4(CDKL4):​c.368T>G​(p.Ile123Ser) 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: CDKL4 ENST00000395035.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26

Genes affected

CDKL4 (HGNC:19287): (cyclin dependent kinase like 4) Predicted to enable cyclin-dependent protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. Predicted to be located in cytoplasm. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL4	NM_001346911.1	c.368T>G	p.Ile123Ser	missense_variant	Exon 4 of 9		NP_001333840.1
CDKL4	NM_001397900.1	c.368T>G	p.Ile123Ser	missense_variant	Exon 5 of 10		NP_001384829.1
CDKL4	NM_001009565.2	c.368T>G	p.Ile123Ser	missense_variant	Exon 4 of 8		NP_001009565.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL4	ENST00000451199.7	c.368T>G	p.Ile123Ser	missense_variant	Exon 5 of 10	2		ENSP00000389833.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000745 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.368T>G (p.I123S) alteration is located in exon 4 (coding exon 4) of the CDKL4 gene. This alteration results from a T to G substitution at nucleotide position 368, causing the isoleucine (I) at amino acid position 123 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	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	.;D
Vest4		0.77
MVP		0.89
MPC		0.59
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.47		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1677055215; hg19: chr2-39431754;