rs35478150

chrX-18619962-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001323289.2(CDKL5):c.2372A>C(p.Gln791Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 1,127,311 control chromosomes in the GnomAD database, including 931 homozygotes. There are 14,285 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q791E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.032 (65 hom., 938 hem., cov: 23)
  • Exomes 𝑓: 0.045 (866 hom. 13347 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 7.36

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007584989).
• BP6: Variant X-18619962-A-C is Benign according to our data. Variant chrX-18619962-A-C is described in ClinVar as [Benign]. Clinvar id is 136713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18619962-A-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.2372A>C	p.Gln791Pro	missense_variant	16/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.2372A>C	p.Gln791Pro	missense_variant	17/22
CDKL5	NM_003159.3	c.2372A>C	p.Gln791Pro	missense_variant	16/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.2372A>C	p.Gln791Pro	missense_variant	16/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 3600 AN: 112544 Hom.: 65 Cov.: 23 AF XY: 0.0270 AC XY: 938 AN XY: 34680

Gnomad AFR AF: 0.00696

Gnomad AMI AF: 0.00871

Gnomad AMR AF: 0.0248

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.0515

Gnomad OTH AF: 0.0331

GnomAD3 exomes AF: 0.0313 AC: 5337 AN: 170666 Hom.: 97 AF XY: 0.0311 AC XY: 1792 AN XY: 57712

Gnomad AFR exome AF: 0.00564

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.0635

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0117

Gnomad FIN exome AF: 0.0212

Gnomad NFE exome AF: 0.0502

Gnomad OTH exome AF: 0.0318

GnomAD4 exome AF: 0.0452 AC: 45855 AN: 1014712 Hom.: 866 Cov.: 22 AF XY: 0.0448 AC XY: 13347 AN XY: 298150

Gnomad4 AFR exome AF: 0.00529

Gnomad4 AMR exome AF: 0.0149

Gnomad4 ASJ exome AF: 0.0656

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.0217

Gnomad4 NFE exome AF: 0.0527

Gnomad4 OTH exome AF: 0.0420

GnomAD4 genome AF: 0.0320 AC: 3602 AN: 112599 Hom.: 65 Cov.: 23 AF XY: 0.0270 AC XY: 938 AN XY: 34745

Gnomad4 AFR AF: 0.00695

Gnomad4 AMR AF: 0.0248

Gnomad4 ASJ AF: 0.0649

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0103

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.0516

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0486 Hom.: 2755

Bravo AF: 0.0310

TwinsUK AF: 0.0539 AC: 200

ALSPAC AF: 0.0492 AC: 142

ESP6500AA AF: 0.00576 AC: 22

ESP6500EA AF: 0.0487 AC: 326

ExAC AF: 0.0321 AC: 3881

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 20, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	curation	RettBASE	May 15, 2014	Common polymorphism -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 13, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Developmental and epileptic encephalopathy, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

History of neurodevelopmental disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2015

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.059	T;T;T;.
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0076	T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.0	M;.;M;M
MutationTaster	Benign	0.022	P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N;.;N;.
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Uncertain	0.0060	D;.;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.64
MPC		0.52
ClinPred		0.026	T
GERP RS		5.5
Varity_R		0.79
gMVP		0.34

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: rs35478150; hg19: chrX-18638082;