X-18507103-A-T

Variant names:

• chrX-18507103-A-T
• rs138539908
• NM_001323289.2:c.7A>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001323289.2(CDKL5):​c.7A>T​(p.Ile3Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000921 in 1,194,152 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000083 (0 hom. 2 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

Genes affected

CDKL5 (HGNC:11411): (cyclin dependent kinase like 5) This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations in this gene have been associated with X-linked infantile spasm syndrome (ISSX), also known as X-linked West syndrome, and Rett syndrome (RTT). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19566548).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.7A>T	p.Ile3Phe	missense_variant	Exon 2 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.7A>T	p.Ile3Phe	missense_variant	Exon 3 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.7A>T	p.Ile3Phe	missense_variant	Exon 2 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.7A>T	p.Ile3Phe	missense_variant	Exon 2 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111392 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33558

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183209 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67667

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000831 AC: 9 AN: 1082708 Hom.: 0 Cov.: 26 AF XY: 0.00000572 AC XY: 2 AN XY: 349496

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000109

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111444 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33620

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Uncertain:1

Jun 21, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is present in population databases (rs138539908, ExAC 0.02%) but has not been reported in the literature in individuals with a CDKL5-related disease. This sequence change replaces isoleucine with phenylalanine at codon 3 of the CDKL5 protein (p.Ile3Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T;T;.;T;T;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.18	N;.;.;N;.;.;.;.;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.70	N;.;.;N;.;.;.;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;.;.;D;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;.;.;D;.;T;T;D;D
Polyphen		1.0	D;.;.;D;.;.;.;.;.
Vest4		0.59
MVP		0.91
MPC		2.3
ClinPred		0.62	D
GERP RS		5.4
Varity_R		0.41
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs138539908; hg19: chrX-18525223;