2-39190413-C-T

Variant names:

• chr2-39190413-C-T
• ENST00000395035.4:c.544G>A

Variant summary

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

The NM_001346911.1(CDKL4):​c.544G>A​(p.Val182Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 12/21 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: CDKL4 NM_001346911.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL4	NM_001346911.1	c.544G>A	p.Val182Ile	missense_variant	Exon 5 of 9		NP_001333840.1
CDKL4	NM_001397900.1	c.544G>A	p.Val182Ile	missense_variant	Exon 6 of 10		NP_001384829.1
CDKL4	NM_001009565.2	c.544G>A	p.Val182Ile	missense_variant	Exon 5 of 8		NP_001009565.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL4	ENST00000451199.7	c.544G>A	p.Val182Ile	missense_variant	Exon 6 of 10	2		ENSP00000389833.2

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

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.544G>A (p.V182I) alteration is located in exon 5 (coding exon 5) of the CDKL4 gene. This alteration results from a G to A substitution at nucleotide position 544, causing the valine (V) at amino acid position 182 to be replaced by an isoleucine (I). 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	0.098
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0086	T
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.44	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.079
Sift	Benign	0.042	D;D
Sift4G	Benign	0.073	T;T
Polyphen		0.0080	.;B
Vest4		0.26
MutPred		0.71		Loss of phosphorylation at Y178 (P = 0.1018);Loss of phosphorylation at Y178 (P = 0.1018);
MVP		0.22
MPC		0.12
ClinPred		0.49	T
GERP RS		3.4
Varity_R		0.10
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr2-39417554;