NM_001323289.2:c.-163+16803_-163+16817delTTTTGTTTTGTTTTG

Variant names:

• chrX-18442467-TTTTTGTTTTGTTTTG-T
• rs60114040
• NM_001323289.2:c.-163+16803_-163+16817delTTTTGTTTTGTTTTG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001323289.2(CDKL5):​c.-163+16803_-163+16817delTTTTGTTTTGTTTTG variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (9 hom., 135 hem., cov: 18)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.942
• 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 -10 ACMG points.

• BP6: Variant X-18442467-TTTTTGTTTTGTTTTG-T is Benign according to our data. Variant chrX-18442467-TTTTTGTTTTGTTTTG-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1253979.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00653 (702/107483) while in subpopulation AFR AF = 0.0216 (630/29154). AF 95% confidence interval is 0.0202. There are 9 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High AC in GnomAd4 at 702 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+16803_-163+16817delTTTTGTTTTGTTTTG		intron	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.-163+75_-163+89delTTTTGTTTTGTTTTG		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.-163+16803_-163+16817delTTTTGTTTTGTTTTG		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+16773_-163+16787delTTTTGTTTTGTTTTG		intron	N/A	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.-163+45_-163+59delTTTTGTTTTGTTTTG		intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.-163+16773_-163+16787delTTTTGTTTTGTTTTG		intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.00650 AC: 698 AN: 107436 Hom.: 9 Cov.: 18

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00337

Gnomad ASJ AF: 0.000391

Gnomad EAS AF: 0.000584

Gnomad SAS AF: 0.00480

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00442

Gnomad NFE AF: 0.000290

Gnomad OTH AF: 0.00489

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 223 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 103

African (AFR) AF: 0.00 AC: 0 AN: 11

American (AMR) AF: 0.00 AC: 0 AN: 7

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 182

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.00653 AC: 702 AN: 107483 Hom.: 9 Cov.: 18 AF XY: 0.00439 AC XY: 135 AN XY: 30781

African (AFR) AF: 0.0216 AC: 630 AN: 29154

American (AMR) AF: 0.00336 AC: 34 AN: 10113

Ashkenazi Jewish (ASJ) AF: 0.000391 AC: 1 AN: 2560

East Asian (EAS) AF: 0.000586 AC: 2 AN: 3414

South Asian (SAS) AF: 0.00482 AC: 12 AN: 2491

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5646

Middle Eastern (MID) AF: 0.00488 AC: 1 AN: 205

European-Non Finnish (NFE) AF: 0.000290 AC: 15 AN: 51793

Other (OTH) AF: 0.00483 AC: 7 AN: 1450

Alfa AF: 0.00 Hom.: 111

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
PhyloP100		0.94
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs60114040; hg19: chrX-18460587;