rs199814742

Variant names:

• chrX-18564539-A-G
• rs199814742
• NM_001323289.2:c.145+17A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001323289.2(CDKL5):​c.145+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 623,579 control chromosomes in the GnomAD database, including 30 homozygotes. There are 1,116 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., 118 hem., cov: 21)
  • Exomes 𝑓: 0.0060 (28 hom. 998 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.180
• Publications: 1 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 (BayesDel_noAF=-0.91).
• BP6: Variant X-18564539-A-G is Benign according to our data. Variant chrX-18564539-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00357 (381/106814) while in subpopulation NFE AF = 0.00448 (233/52042). AF 95% confidence interval is 0.00401. There are 2 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 381 XL,AD gene.

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.145+17A>G		intron	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.145+17A>G		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.145+17A>G		intron	N/A	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.145+17A>G		intron	N/A	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.145+17A>G		intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.145+17A>G		intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 383 AN: 106819 Hom.: 2 Cov.: 21

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

Gnomad ASJ AF: 0.0298

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00366

Gnomad FIN AF: 0.00430

Gnomad MID AF: 0.0429

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.00561

GnomAD2 exomes AF: 0.00980 AC: 645 AN: 65810 AF XY: 0.0124

Gnomad AFR exome AF: 0.00364

Gnomad AMR exome AF: 0.00570

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0159

GnomAD4 exome AF: 0.00600 AC: 3101 AN: 516765 Hom.: 28 Cov.: 8 AF XY: 0.00888 AC XY: 998 AN XY: 112335

African (AFR) AF: 0.00153 AC: 18 AN: 11796

American (AMR) AF: 0.00466 AC: 71 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.0387 AC: 432 AN: 11153

East Asian (EAS) AF: 0.00 AC: 0 AN: 17740

South Asian (SAS) AF: 0.00407 AC: 74 AN: 18179

European-Finnish (FIN) AF: 0.00534 AC: 136 AN: 25485

Middle Eastern (MID) AF: 0.0125 AC: 23 AN: 1839

European-Non Finnish (NFE) AF: 0.00556 AC: 2180 AN: 392318

Other (OTH) AF: 0.00725 AC: 167 AN: 23027

GnomAD4 genome AF: 0.00357 AC: 381 AN: 106814 Hom.: 2 Cov.: 21 AF XY: 0.00394 AC XY: 118 AN XY: 29966

African (AFR) AF: 0.000339 AC: 10 AN: 29528

American (AMR) AF: 0.00133 AC: 13 AN: 9780

Ashkenazi Jewish (ASJ) AF: 0.0298 AC: 78 AN: 2621

East Asian (EAS) AF: 0.00 AC: 0 AN: 3432

South Asian (SAS) AF: 0.00369 AC: 9 AN: 2440

European-Finnish (FIN) AF: 0.00430 AC: 20 AN: 4651

Middle Eastern (MID) AF: 0.0476 AC: 10 AN: 210

European-Non Finnish (NFE) AF: 0.00448 AC: 233 AN: 52042

Other (OTH) AF: 0.00555 AC: 8 AN: 1441

Alfa AF: 0.00695 Hom.: 54

Bravo AF: 0.00322

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Developmental and epileptic encephalopathy, 2 (2)
-	-	1	CDKL5 disorder (1)
-	-	1	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.77
DANN	Benign	0.54
PhyloP100		-0.18
Mutation Taster		=100/0	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: rs199814742; hg19: chrX-18582659;