X-18442467-TTTTTGTTTTGTTTTGTTTTGTTTTG-TTTTTGTTTTGTTTTG

Variant names:

• chrX-18442467-TTTTTGTTTTG-T
• rs60114040
• NM_001323289.2:c.-163+16808_-163+16817delTTTTGTTTTG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001323289.2(CDKL5):​c.-163+16808_-163+16817delTTTTGTTTTG variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0095 (8 hom., 189 hem., cov: 18)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00947 (1018/107480) while in subpopulation AFR AF = 0.024 (699/29157). AF 95% confidence interval is 0.0225. There are 8 homozygotes in GnomAd4. There are 189 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1018 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.-163+16808_-163+16817delTTTTGTTTTG		intron_variant	Intron 1 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.-163+80_-163+89delTTTTGTTTTG		intron_variant	Intron 2 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.-163+16808_-163+16817delTTTTGTTTTG		intron_variant	Intron 1 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.-163+16773_-163+16782delTTTTGTTTTG		intron_variant	Intron 1 of 17	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes AF: 0.00947 AC: 1017 AN: 107434 Hom.: 8 Cov.: 18

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00267

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00526

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.000886

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00382

Gnomad OTH AF: 0.00978

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: 0.00947 AC: 1018 AN: 107480 Hom.: 8 Cov.: 18 AF XY: 0.00614 AC XY: 189 AN XY: 30780

African (AFR) AF: 0.0240 AC: 699 AN: 29157

American (AMR) AF: 0.00267 AC: 27 AN: 10112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2560

East Asian (EAS) AF: 0.00527 AC: 18 AN: 3414

South Asian (SAS) AF: 0.0229 AC: 57 AN: 2491

European-Finnish (FIN) AF: 0.000886 AC: 5 AN: 5646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 205

European-Non Finnish (NFE) AF: 0.00382 AC: 198 AN: 51788

Other (OTH) AF: 0.00966 AC: 14 AN: 1450

Alfa AF: 0.000295 Hom.: 111

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;