rs201473442

Positions:

• chrX-18628526-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001323289.2(CDKL5):​c.2652C>T​(p.Gly884Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,210,414 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 60 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 6 hem., cov: 22)
  • Exomes 𝑓: 0.00015 (0 hom. 54 hem.)
• Consequence: CDKL5 NM_001323289.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0290

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant X-18628526-C-T is Benign according to our data. Variant chrX-18628526-C-T is described in ClinVar as [Benign]. Clinvar id is 464815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.029 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000232 (26/112199) while in subpopulation EAS AF= 0.00226 (8/3544). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2652C>T	p.Gly884Gly	synonymous_variant	18/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2652C>T	p.Gly884Gly	synonymous_variant	19/22		NP_001032420.1
CDKL5	NM_003159.3	c.2652C>T	p.Gly884Gly	synonymous_variant	18/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2652C>T	p.Gly884Gly	synonymous_variant	18/18	1	NM_001323289.2	ENSP00000485244.1
CDKL5	ENST00000379989.6	c.2652C>T	p.Gly884Gly	synonymous_variant	19/22	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2652C>T	p.Gly884Gly	synonymous_variant	18/21	1		ENSP00000369332.3
CDKL5	ENST00000674046.1	c.2775C>T	p.Gly925Gly	synonymous_variant	19/19			ENSP00000501174.1

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 26 AN: 112144 Hom.: 0 Cov.: 22 AF XY: 0.000175 AC XY: 6 AN XY: 34310

Gnomad AFR AF: 0.000517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00225

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000338 AC: 62 AN: 183303 Hom.: 0 AF XY: 0.000266 AC XY: 18 AN XY: 67773

Gnomad AFR exome AF: 0.000532

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00368

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000147 AC: 161 AN: 1098215 Hom.: 0 Cov.: 32 AF XY: 0.000149 AC XY: 54 AN XY: 363569

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00311

Gnomad4 SAS exome AF: 0.000222

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000356

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.000232 AC: 26 AN: 112199 Hom.: 0 Cov.: 22 AF XY: 0.000175 AC XY: 6 AN XY: 34375

Gnomad4 AFR AF: 0.000516

Gnomad4 AMR AF: 0.000188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00226

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000487

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.2
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs201473442; hg19: chrX-18646646; COSMIC: COSV66111355; COSMIC: COSV66111355;