rs747799506

Variant names:

• chrX-18650508-G-A
• rs747799506
• ENST00000379989.6:c.2896G>A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BA1 BP4 BS2_Supporting BP5

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Val966Ile variant in CDKL5 is 0.03% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Val966Ile variant is observed in at least 1 unaffected individual (internal database) (BS2_supporting). Computational analysis prediction tools suggest that the p.Val966Ile variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Val966Ile variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Val966Ile variant in CDKL5 is classified as benign based on the ACMG/AMP criteria applied (BA1, BS2_supporting, BP4, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA209185/MONDO:0100039/016

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000046 (0 hom. 22 hem.)
• Consequence: CDKL5 NM_003159.3 missense
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: -0.0330

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 -11 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4	c.185-3176C>T		intron_variant	Intron 3 of 5	ENST00000379984.4	NP_000321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.185-3176C>T		intron_variant	Intron 3 of 5	1	NM_000330.4	ENSP00000369320.3

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112374 Hom.: 0 Cov.: 24 AF XY: 0.0000290 AC XY: 1 AN XY: 34520

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000327 AC: 6 AN: 183481 Hom.: 0 AF XY: 0.0000589 AC XY: 4 AN XY: 67911

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000314

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000464 AC: 51 AN: 1098012 Hom.: 0 Cov.: 30 AF XY: 0.0000605 AC XY: 22 AN XY: 363382

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000425

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000321

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112374 Hom.: 0 Cov.: 24 AF XY: 0.0000290 AC XY: 1 AN XY: 34520

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000368

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

CDKL5 disorder Benign:2

Jul 12, 2024

Centre for Population Genomics, CPG

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). -

Mar 26, 2021

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The allele frequency of the p.Val966Ile variant in CDKL5 is 0.03% in South Asian sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Val966Ile variant is observed in at least 1 unaffected individual (internal database) (BS2_supporting). Computational analysis prediction tools suggest that the p.Val966Ile variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Val966Ile variant is found in a patient with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Val966Ile variant in CDKL5 is classified as benign based on the ACMG/AMP criteria applied (BA1, BS2_supporting, BP4, BP5). -

not specified Benign:1

Feb 04, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 2 Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 24, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23756444, 23242510) -

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

Jun 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.6
DANN	Benign	0.93
DEOGEN2	Benign	0.025	T;T
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.42	.;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.10
Sift	Benign	0.039	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0080	B;B
Vest4		0.053
MVP		0.29
MPC		0.33
ClinPred		0.026	T
GERP RS		1.0
Varity_R		0.055
gMVP		0.034

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: rs747799506; hg19: chrX-18668628;