rs587783404

Variant names:

• chrX-18579835-A-G
• rs587783404
• NM_001323289.2:c.283-13A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.283-13 A>G variant in CDKL5 is 0.036% in Latino sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). In summary, the c.283-13 A>G variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA171639/MONDO:0100039/033

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000017 (0 hom. 6 hem.)
• Consequence: CDKL5 NM_003159.3 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:3
• Conservation: PhyloP100: -0.259
• Publications: 0 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 -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003159.3. 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.283-13A>G		intron	N/A	NP_001310218.1
	CDKL5	NM_001037343.2		c.283-13A>G		intron	N/A	NP_001032420.1
	CDKL5	NM_003159.3		c.283-13A>G		intron	N/A	NP_003150.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.283-13A>G		intron	N/A	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.283-13A>G		intron	N/A	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.283-13A>G		intron	N/A	ENSP00000369332.3

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 11 AN: 111705 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000478

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: 0.0000377

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.0000712 AC: 13 AN: 182610 AF XY: 0.0000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000330

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000174 AC: 19 AN: 1090730 Hom.: 0 Cov.: 27 AF XY: 0.0000168 AC XY: 6 AN XY: 357214

African (AFR) AF: 0.00 AC: 0 AN: 26219

American (AMR) AF: 0.000256 AC: 9 AN: 35138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19272

East Asian (EAS) AF: 0.00 AC: 0 AN: 30068

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53861

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.00000598 AC: 5 AN: 835791

Other (OTH) AF: 0.0000873 AC: 4 AN: 45809

GnomAD4 genome AF: 0.0000985 AC: 11 AN: 111705 Hom.: 0 Cov.: 23 AF XY: 0.000148 AC XY: 5 AN XY: 33897

African (AFR) AF: 0.0000649 AC: 2 AN: 30813

American (AMR) AF: 0.000478 AC: 5 AN: 10456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.00 AC: 0 AN: 2680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6033

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53061

Other (OTH) AF: 0.00133 AC: 2 AN: 1508

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.000215

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.16
DANN	Benign	0.72
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism

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: rs587783404; hg19: chrX-18597955;