rs786204996

Variant names:

• chrX-18425418-G-T
• rs777401314
• NM_001323289.2:c.-440G>T

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.-440G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 113,114 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 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 0.00048 (0 hom., 21 hem., cov: 24)
• Consequence: CDKL5 NM_001323289.2 upstream_gene
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 1.92
• 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=-0.74).
• BP6: Variant X-18425418-G-T is Benign according to our data. Variant chrX-18425418-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 189604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000477 (54/113114) while in subpopulation SAS AF = 0.00181 (5/2770). AF 95% confidence interval is 0.000711. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 54 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.-440G>T		upstream_gene	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_003159.3		c.-440G>T		upstream_gene	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.-440G>T		upstream_gene	N/A	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379996.7	TSL:1	c.-440G>T		upstream_gene	N/A	ENSP00000369332.3	O76039-1
	CDKL5	ENST00000674046.1		c.-440G>T		upstream_gene	N/A	ENSP00000501174.1	A0A669KBC2

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 55 AN: 113064 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000963

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00216

Gnomad FIN AF: 0.000796

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000731

Gnomad OTH AF: 0.00130

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

GnomAD4 genome AF: 0.000477 AC: 54 AN: 113114 Hom.: 0 Cov.: 24 AF XY: 0.000596 AC XY: 21 AN XY: 35260

African (AFR) AF: 0.0000961 AC: 3 AN: 31233

American (AMR) AF: 0.00 AC: 0 AN: 10829

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3556

South Asian (SAS) AF: 0.00181 AC: 5 AN: 2770

European-Finnish (FIN) AF: 0.000796 AC: 5 AN: 6284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000731 AC: 39 AN: 53326

Other (OTH) AF: 0.00129 AC: 2 AN: 1556

Alfa AF: 0.000648 Hom.: 2

Bravo AF: 0.000529

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Atypical Rett syndrome (1)
-	-	1	CDKL5 disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Benign	0.83
PhyloP100		1.9
PromoterAI		-0.030	Neutral

Splicing

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

Other links and lift over

dbSNP: rs777401314; hg19: chrX-18443538;