ENST00000395035.4:c.103T>A

Variant names:

• chr2-39229430-A-T
• rs772678564
• NM_001397900.1:c.103T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000395035.4(CDKL4):​c.103T>A​(p.Phe35Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CDKL4 ENST00000395035.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.60
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395035.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL4	NM_001397900.1	MANE Select	c.103T>A	p.Phe35Ile	missense	Exon 2 of 10	NP_001384829.1	H7BZI6
	CDKL4	NM_001346911.1		c.103T>A	p.Phe35Ile	missense	Exon 1 of 9	NP_001333840.1	Q5MAI5-1
	CDKL4	NM_001009565.3		c.103T>A	p.Phe35Ile	missense	Exon 2 of 9	NP_001009565.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL4	ENST00000451199.7	TSL:2 MANE Select	c.103T>A	p.Phe35Ile	missense	Exon 2 of 10	ENSP00000389833.2	H7BZI6
	CDKL4	ENST00000395035.4	TSL:1	c.103T>A	p.Phe35Ile	missense	Exon 2 of 10	ENSP00000378476.3	Q5MAI5-1
	CDKL4	ENST00000378803.6	TSL:1	c.103T>A	p.Phe35Ile	missense	Exon 2 of 9	ENSP00000368080.1	Q5MAI5-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250476 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460846 Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8 AN XY: 726680

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86034

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111630

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.47	N
PhyloP100		8.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.52		Loss of catalytic residue at F35 (P = 0.0489)
MVP		0.48
MPC		0.66
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.89
gMVP		0.28
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs772678564; hg19: chr2-39456571;