X-18564526-GATATATATATATAT-GATATATATATATATAT

Variant names:

• chrX-18564526-G-GAT
• rs745969938
• NM_001323289.2:c.145+27_145+28dupAT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000623535.2(CDKL5):​c.145+4_145+5insAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (4 hom., 177 hem., cov: 19)
  • Exomes 𝑓: 0.061 (0 hom. 55 hem.)
• Consequence: CDKL5 ENST00000623535.2 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.405
• 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 -16 ACMG points.

• BP6: Variant X-18564526-G-GAT is Benign according to our data. Variant chrX-18564526-G-GAT is described in ClinVar as Benign. ClinVar VariationId is 414804.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 = 0.0122 (1138/92992) while in subpopulation SAS AF = 0.0206 (42/2034). AF 95% confidence interval is 0.0157. There are 4 homozygotes in GnomAd4. There are 177 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1138 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000623535.2. 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.145+27_145+28dupAT		intron	N/A	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.145+27_145+28dupAT		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.145+27_145+28dupAT		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.145+4_145+5insAT		splice_region intron	N/A	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.145+4_145+5insAT		splice_region intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.145+4_145+5insAT		splice_region intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1140 AN: 93017 Hom.: 4 Cov.: 19

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.00388

Gnomad EAS AF: 0.0159

Gnomad SAS AF: 0.0204

Gnomad FIN AF: 0.00949

Gnomad MID AF: 0.00498

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0190

GnomAD2 exomes AF: 0.0517 AC: 3755 AN: 72668 AF XY: 0.000463

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0266

Gnomad ASJ exome AF: 0.0937

Gnomad EAS exome AF: 0.0224

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.0519

Gnomad OTH exome AF: 0.0453

GnomAD4 exome AF: 0.0609 AC: 28132 AN: 461766 Hom.: 0 Cov.: 5 AF XY: 0.000591 AC XY: 55 AN XY: 93086

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0545 AC: 675 AN: 12374

American (AMR) AF: 0.0311 AC: 736 AN: 23695

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 685 AN: 10760

East Asian (EAS) AF: 0.0627 AC: 1091 AN: 17399

South Asian (SAS) AF: 0.0346 AC: 892 AN: 25756

European-Finnish (FIN) AF: 0.0655 AC: 1617 AN: 24704

Middle Eastern (MID) AF: 0.0540 AC: 99 AN: 1832

European-Non Finnish (NFE) AF: 0.0649 AC: 21009 AN: 323769

Other (OTH) AF: 0.0618 AC: 1328 AN: 21477

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0122 AC: 1138 AN: 92992 Hom.: 4 Cov.: 19 AF XY: 0.00759 AC XY: 177 AN XY: 23320

African (AFR) AF: 0.0146 AC: 374 AN: 25671

American (AMR) AF: 0.0158 AC: 131 AN: 8285

Ashkenazi Jewish (ASJ) AF: 0.00388 AC: 9 AN: 2321

East Asian (EAS) AF: 0.0159 AC: 47 AN: 2947

South Asian (SAS) AF: 0.0206 AC: 42 AN: 2034

European-Finnish (FIN) AF: 0.00949 AC: 33 AN: 3479

Middle Eastern (MID) AF: 0.00556 AC: 1 AN: 180

European-Non Finnish (NFE) AF: 0.0103 AC: 478 AN: 46262

Other (OTH) AF: 0.0189 AC: 23 AN: 1218

Alfa AF: 0.0360 Hom.: 26

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs745969938; hg19: chrX-18582646;