rs150900695

Positions:

• chrX-18653445-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 ENST00000379989.6(CDKL5):​c.2994C>T​(p.Phe998=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00043 in 1,209,395 control chromosomes in the GnomAD database, including 3 homozygotes. There are 124 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., 65 hem., cov: 23)
  • Exomes 𝑓: 0.00025 (2 hom. 59 hem.)
• Consequence: CDKL5 ENST00000379989.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.119

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]

RS1 (HGNC:10457): (retinoschisin 1) This gene encodes an extracellular protein that plays a crucial role in the cellular organization of the retina. The encoded protein is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Mutations in this gene are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-18653445-C-T is Benign according to our data. Variant chrX-18653445-C-T is described in ClinVar as [Benign]. Clinvar id is 136716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.119 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00223 (249/111722) while in subpopulation AFR AF= 0.00738 (227/30742). AF 95% confidence interval is 0.0066. There are 1 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 65 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RS1	NM_000330.4	c.184+3208G>A		intron_variant		ENST00000379984.4
CDKL5	NM_001037343.2	c.2994C>T	p.Phe998=	synonymous_variant	22/22
CDKL5	NM_003159.3	c.2994C>T	p.Phe998=	synonymous_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000379989.6	c.2994C>T	p.Phe998=	synonymous_variant	22/22	1
CDKL5	ENST00000379996.7	c.2994C>T	p.Phe998=	synonymous_variant	21/21	1
RS1	ENST00000379984.4	c.184+3208G>A		intron_variant		1	NM_000330.4	P1
CDKL5	ENST00000673617.1	n.266C>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 249 AN: 111670 Hom.: 1 Cov.: 23 AF XY: 0.00192 AC XY: 65 AN XY: 33834

Gnomad AFR AF: 0.00740

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00162

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00201

GnomAD3 exomes AF: 0.000577 AC: 105 AN: 181879 Hom.: 0 AF XY: 0.000406 AC XY: 27 AN XY: 66439

Gnomad AFR exome AF: 0.00736

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000247

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000247 AC: 271 AN: 1097673 Hom.: 2 Cov.: 31 AF XY: 0.000162 AC XY: 59 AN XY: 363083

Gnomad4 AFR exome AF: 0.00762

Gnomad4 AMR exome AF: 0.000341

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000166

Gnomad4 OTH exome AF: 0.000760

GnomAD4 genome AF: 0.00223 AC: 249 AN: 111722 Hom.: 1 Cov.: 23 AF XY: 0.00192 AC XY: 65 AN XY: 33896

Gnomad4 AFR AF: 0.00738

Gnomad4 AMR AF: 0.00162

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00198

Alfa AF: 0.00109 Hom.: 4

Bravo AF: 0.00245

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 23, 2018

- -

History of neurodevelopmental disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2016

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.0
DANN	Benign	0.59

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: rs150900695; hg19: chrX-18671565; COSMIC: COSV66106493; COSMIC: COSV66106493;