rs187188170

Variant names:

• chrX-18425831-T-C
• rs187188170
• NM_001323289.2:c.-163+136T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001323289.2(CDKL5):​c.-163+136T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 112,405 control chromosomes in the GnomAD database, including 12 homozygotes. There are 413 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 0.013 (12 hom., 411 hem., cov: 24)
  • Exomes 𝑓: 0.015 (0 hom. 2 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.262
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-18425831-T-C is Benign according to our data. Variant chrX-18425831-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1189327.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1469/112271) while in subpopulation AFR AF = 0.0331 (1026/31002). AF 95% confidence interval is 0.0314. There are 12 homozygotes in GnomAd4. There are 411 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1469 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.-163+136T>C		intron	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_003159.3		c.-163+136T>C		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.-163+136T>C		intron	N/A	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379996.7	TSL:1	c.-163+136T>C		intron	N/A	ENSP00000369332.3	O76039-1
	CDKL5	ENST00000674046.1		c.-163+136T>C		intron	N/A	ENSP00000501174.1	A0A669KBC2

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1471 AN: 112229 Hom.: 12 Cov.: 24

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00585

Gnomad ASJ AF: 0.0295

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00363

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.0460

Gnomad NFE AF: 0.00449

Gnomad OTH AF: 0.0145

GnomAD4 exome AF: 0.0149 AC: 2 AN: 134 Hom.: 0 AF XY: 0.0286 AC XY: 2 AN XY: 70

African (AFR) AF: 0.00 AC: 0 AN: 3

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 3

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00840 AC: 1 AN: 119

Other (OTH) AF: 0.143 AC: 1 AN: 7

GnomAD4 genome AF: 0.0131 AC: 1469 AN: 112271 Hom.: 12 Cov.: 24 AF XY: 0.0119 AC XY: 411 AN XY: 34569

African (AFR) AF: 0.0331 AC: 1026 AN: 31002

American (AMR) AF: 0.00584 AC: 63 AN: 10790

Ashkenazi Jewish (ASJ) AF: 0.0295 AC: 78 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3466

South Asian (SAS) AF: 0.00364 AC: 10 AN: 2746

European-Finnish (FIN) AF: 0.00368 AC: 23 AN: 6244

Middle Eastern (MID) AF: 0.0505 AC: 11 AN: 218

European-Non Finnish (NFE) AF: 0.00446 AC: 236 AN: 52954

Other (OTH) AF: 0.0143 AC: 22 AN: 1537

Alfa AF: 0.00936 Hom.: 38

Bravo AF: 0.0146

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.3
DANN	Benign	0.49
PhyloP100		-0.26
PromoterAI		-0.051	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs187188170; hg19: chrX-18443951;