rs267608629

chrX-18604306-A-GchrX-18604306-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001323289.2(CDKL5):c.1382A>G(p.Asn461Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,209,668 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N461I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 3 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.04

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023553222).
• BP6: Variant X-18604306-A-G is Benign according to our data. Variant chrX-18604306-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 143776.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.1382A>G	p.Asn461Ser	missense_variant	12/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.1382A>G	p.Asn461Ser	missense_variant	13/22
CDKL5	NM_003159.3	c.1382A>G	p.Asn461Ser	missense_variant	12/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.1382A>G	p.Asn461Ser	missense_variant	12/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111961 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34129

Gnomad AFR AF: 0.0000325

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000219 AC: 4 AN: 182865 Hom.: 0 AF XY: 0.0000296 AC XY: 2 AN XY: 67513

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: 0.000157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1097707 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 3 AN XY: 363113

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111961 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34129

Gnomad4 AFR AF: 0.0000325

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

curation

RettBASE

May 09, 2014

In silico predictions: SIFT = tolerated, MutationTaster = polymorphism, PolyPhen2 = benign, AlignGVGD = benign (C0) -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	8.4
Dann	Benign	0.66
DEOGEN2	Benign	0.018	T;T;.;T;.;.
FATHMM_MKL	Benign	0.25	N
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.024	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;.;.;N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.38	N;.;.;N;.;.
REVEL	Benign	0.13
Sift	Benign	0.58	T;.;.;T;.;.
Sift4G	Benign	0.69	T;.;.;T;T;T
Polyphen		0.0	B;.;.;B;.;.
Vest4		0.083
MutPred		0.12		Gain of phosphorylation at N461 (P = 0.023);Gain of phosphorylation at N461 (P = 0.023);Gain of phosphorylation at N461 (P = 0.023);Gain of phosphorylation at N461 (P = 0.023);Gain of phosphorylation at N461 (P = 0.023);Gain of phosphorylation at N461 (P = 0.023);
MVP		0.47
MPC		0.27
ClinPred		0.0065	T
GERP RS		3.0
Varity_R		0.029
gMVP		0.035

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: rs267608629; hg19: chrX-18622426;