chrX-18584219-ATTTC-A

Variant names:

• chrX-18584219-ATTTC-A
• rs267608481
• NM_001323289.2:c.464-40_464-37delCTTT

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.464-40_464-37delCTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000737 in 884,973 control chromosomes in the GnomAD database, including 2 homozygotes. There are 183 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., 21 hem., cov: 23)
  • Exomes 𝑓: 0.00076 (2 hom. 162 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 1.68
• 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-18584219-ATTTC-A is Benign according to our data. Variant chrX-18584219-ATTTC-A is described in ClinVar as Likely_benign. ClinVar VariationId is 156091.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000581 (65/111958) while in subpopulation NFE AF = 0.000828 (44/53163). AF 95% confidence interval is 0.000633. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 65 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.464-40_464-37delCTTT		intron	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.464-40_464-37delCTTT		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.464-40_464-37delCTTT		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.464-43_464-40delTTTC		intron	N/A	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.464-43_464-40delTTTC		intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.464-43_464-40delTTTC		intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.000581 AC: 65 AN: 111905 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000285

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00248

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000828

Gnomad OTH AF: 0.000661

GnomAD2 exomes AF: 0.000712 AC: 130 AN: 182458 AF XY: 0.000521

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00272

Gnomad NFE exome AF: 0.000910

Gnomad OTH exome AF: 0.000668

GnomAD4 exome AF: 0.000759 AC: 587 AN: 773015 Hom.: 2 AF XY: 0.000730 AC XY: 162 AN XY: 222069

African (AFR) AF: 0.0000495 AC: 1 AN: 20204

American (AMR) AF: 0.000317 AC: 11 AN: 34751

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17378

East Asian (EAS) AF: 0.00 AC: 0 AN: 28736

South Asian (SAS) AF: 0.00 AC: 0 AN: 47610

European-Finnish (FIN) AF: 0.00342 AC: 138 AN: 40303

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3423

European-Non Finnish (NFE) AF: 0.000737 AC: 402 AN: 545340

Other (OTH) AF: 0.000992 AC: 35 AN: 35270

GnomAD4 genome AF: 0.000581 AC: 65 AN: 111958 Hom.: 0 Cov.: 23 AF XY: 0.000615 AC XY: 21 AN XY: 34160

African (AFR) AF: 0.0000648 AC: 2 AN: 30873

American (AMR) AF: 0.000285 AC: 3 AN: 10540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2697

European-Finnish (FIN) AF: 0.00248 AC: 15 AN: 6037

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000828 AC: 44 AN: 53163

Other (OTH) AF: 0.000653 AC: 1 AN: 1531

Alfa AF: 0.000763 Hom.: 6

Bravo AF: 0.000412

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs267608481; hg19: chrX-18602339;