rs35478150

Variant names:

• chrX-18619962-A-C
• rs35478150
• NM_001323289.2:c.2372A>C

Variant summary

Our verdict is Benign. The variant received -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:13
• Conservation: PhyloP100: 7.36
• Publications: 15 publications found

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]

CDKL5 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 136713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323289.2. 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
	CDKL5	NM_001323289.2	MANE Select	c.2372A>C	p.Gln791Pro	missense	Exon 16 of 18	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.2372A>C	p.Gln791Pro	missense	Exon 17 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2372A>C	p.Gln791Pro	missense	Exon 16 of 21	NP_003150.1	O76039-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.2372A>C	p.Gln791Pro	missense	Exon 16 of 18	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.2372A>C	p.Gln791Pro	missense	Exon 17 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2372A>C	p.Gln791Pro	missense	Exon 16 of 21	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 3600 AN: 112544 Hom.: 65 Cov.: 23

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

GnomAD2 exomes AF: 0.0313 AC: 5337 AN: 170666 AF XY: 0.0311

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 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

African (AFR) AF: 0.00529 AC: 132 AN: 24963

American (AMR) AF: 0.0149 AC: 517 AN: 34607

Ashkenazi Jewish (ASJ) AF: 0.0656 AC: 1229 AN: 18745

East Asian (EAS) AF: 0.00 AC: 0 AN: 29805

South Asian (SAS) AF: 0.0134 AC: 680 AN: 50925

European-Finnish (FIN) AF: 0.0217 AC: 871 AN: 40219

Middle Eastern (MID) AF: 0.0340 AC: 131 AN: 3857

European-Non Finnish (NFE) AF: 0.0527 AC: 40481 AN: 768349

Other (OTH) AF: 0.0420 AC: 1814 AN: 43242

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

African (AFR) AF: 0.00695 AC: 216 AN: 31099

American (AMR) AF: 0.0248 AC: 265 AN: 10680

Ashkenazi Jewish (ASJ) AF: 0.0649 AC: 172 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3601

South Asian (SAS) AF: 0.0103 AC: 28 AN: 2722

European-Finnish (FIN) AF: 0.0187 AC: 115 AN: 6147

Middle Eastern (MID) AF: 0.0183 AC: 4 AN: 218

European-Non Finnish (NFE) AF: 0.0516 AC: 2746 AN: 53265

Other (OTH) AF: 0.0327 AC: 50 AN: 1529

Alfa AF: 0.0452 Hom.: 3217

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	1	CDKL5 disorder (1)
-	-	1	Developmental and epileptic encephalopathy, 2 (1)
-	-	1	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0076	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.64
MPC		0.52
ClinPred		0.026	T
GERP RS		5.5
Varity_R		0.79
gMVP		0.34
Mutation Taster		=97/3	polymorphism (auto)

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: rs35478150; hg19: chrX-18638082;