X-18425834-C-CTT

Variant names:

• chrX-18425834-C-CTT
• rs1401710048
• NM_001323289.2:c.-163+139_-163+140insTT

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+139_-163+140insTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 112,888 control chromosomes in the GnomAD database, including 1 homozygotes. There are 130 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0031 (1 hom., 130 hem., cov: 24)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.296
• 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-18425834-C-CTT is Benign according to our data. Variant chrX-18425834-C-CTT is described in ClinVar as [Likely_benign]. Clinvar id is 1194507.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00314 (354/112888) while in subpopulation NFE AF = 0.00393 (209/53134). AF 95% confidence interval is 0.0035. There are 1 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 354 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.-163+139_-163+140insTT		intron_variant	Intron 1 of 17	ENST00000623535.2	NP_001310218.1
CDKL5	NM_003159.3	c.-163+139_-163+140insTT		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+139_-163+140insTT		intron_variant	Intron 1 of 17	1	NM_001323289.2	ENSP00000485244.1
CDKL5	ENST00000379996.7	c.-163+139_-163+140insTT		intron_variant	Intron 1 of 20	1		ENSP00000369332.3
CDKL5	ENST00000674046.1	c.-163+139_-163+140insTT		intron_variant	Intron 1 of 18			ENSP00000501174.1

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 354 AN: 112840 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.000578

Gnomad AMI AF: 0.0222

Gnomad AMR AF: 0.00212

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.00261

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00314 AC: 354 AN: 112888 Hom.: 1 Cov.: 24 AF XY: 0.00371 AC XY: 130 AN XY: 35072

African (AFR) AF: 0.000577 AC: 18 AN: 31211

American (AMR) AF: 0.00212 AC: 23 AN: 10847

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3502

South Asian (SAS) AF: 0.00 AC: 0 AN: 2806

European-Finnish (FIN) AF: 0.0135 AC: 85 AN: 6293

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00393 AC: 209 AN: 53134

Other (OTH) AF: 0.00258 AC: 4 AN: 1552

Alfa AF: 0.00828 Hom.: 8

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 20, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.30
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: rs1401710048; hg19: chrX-18443954;