rs184407021

Variant names:

• chrX-18425432-C-G
• rs184407021
• NM_001323289.2:c.-426C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-18425432-C-G
• chrX-18425432-C-T

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.-426C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 113,139 control chromosomes in the GnomAD database, including 1 homozygotes. There are 102 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.0033 (1 hom., 102 hem., cov: 25)
• Consequence: CDKL5 NM_001323289.2 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.0410
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-18425432-C-G is Benign according to our data. Variant chrX-18425432-C-G is described in ClinVar as Benign. ClinVar VariationId is 189539.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00326 (369/113139) while in subpopulation NFE AF = 0.00429 (229/53339). AF 95% confidence interval is 0.00384. There are 1 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High AC in GnomAd4 at 369 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.-426C>G		upstream_gene	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_003159.3		c.-426C>G		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.-426C>G		upstream_gene	N/A	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379996.7	TSL:1	c.-426C>G		upstream_gene	N/A	ENSP00000369332.3	O76039-1
	CDKL5	ENST00000674046.1		c.-426C>G		upstream_gene	N/A	ENSP00000501174.1	A0A669KBC2

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 370 AN: 113089 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.000674

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00343

Gnomad ASJ AF: 0.0165

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000717

Gnomad FIN AF: 0.00238

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.00429

Gnomad OTH AF: 0.0117

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

GnomAD4 genome AF: 0.00326 AC: 369 AN: 113139 Hom.: 1 Cov.: 25 AF XY: 0.00289 AC XY: 102 AN XY: 35299

African (AFR) AF: 0.000672 AC: 21 AN: 31237

American (AMR) AF: 0.00342 AC: 37 AN: 10813

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 44 AN: 2663

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.000719 AC: 2 AN: 2782

European-Finnish (FIN) AF: 0.00238 AC: 15 AN: 6302

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 218

European-Non Finnish (NFE) AF: 0.00429 AC: 229 AN: 53339

Other (OTH) AF: 0.0116 AC: 18 AN: 1557

Alfa AF: 0.00114 Hom.: 7

Bravo AF: 0.00339

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CDKL5 disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.9
DANN	Benign	0.49
PhyloP100		-0.041
PromoterAI		0.017	Neutral

Splicing

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

Other links and lift over

dbSNP: rs184407021; hg19: chrX-18443552;