X-18598609-A-G

Position:

• chrX-18598609-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001323289.2(CDKL5):​c.973A>G​(p.Asn325Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,093,541 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.48

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2682542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.973A>G	p.Asn325Asp	missense_variant	11/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.973A>G	p.Asn325Asp	missense_variant	12/22		NP_001032420.1
CDKL5	NM_003159.3	c.973A>G	p.Asn325Asp	missense_variant	11/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.973A>G	p.Asn325Asp	missense_variant	11/18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183258 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67764

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1093541 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 359035

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2017

The p.N325D variant (also known as c.973A>G), located in coding exon 10 of the CDKL5 gene, results from an A to G substitution at nucleotide position 973. The asparagine at codon 325 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 533388). This variant has not been reported in the literature in individuals affected with CDKL5-related conditions. This variant is present in population databases (rs756721244, gnomAD 0.001%). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 325 of the CDKL5 protein (p.Asn325Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.8	L;.;.;L;.;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.3	N;.;.;N;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;.;.;D;.;.
Sift4G	Benign	0.18	T;.;.;T;T;T
Polyphen		0.84	P;.;.;P;.;.
Vest4		0.28
MutPred		0.12		Loss of MoRF binding (P = 0.0461);Loss of MoRF binding (P = 0.0461);Loss of MoRF binding (P = 0.0461);Loss of MoRF binding (P = 0.0461);Loss of MoRF binding (P = 0.0461);Loss of MoRF binding (P = 0.0461);
MVP		0.88
MPC		0.59
ClinPred		0.34	T
GERP RS		5.6
Varity_R		0.66
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs756721244; hg19: chrX-18616729;