rs866859766

chrX-18650592-G-AchrX-18650592-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BP6_Very_Strong

The ENST00000379989.6(CDKL5):c.2980G>A(p.Gly994Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,097,473 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G994A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 3 hem.)
• Consequence: CDKL5 ENST00000379989.6 missense, splice_region
• Scores: Splicing: ADA: 0.9860
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 0.00600

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 -7 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant X-18650592-G-A is Benign according to our data. Variant chrX-18650592-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 375543.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RS1	NM_000330.4	c.185-3260C>T		intron_variant		ENST00000379984.4
CDKL5	NM_001037343.2	c.2980G>A	p.Gly994Arg	missense_variant, splice_region_variant	21/22
CDKL5	NM_003159.3	c.2980G>A	p.Gly994Arg	missense_variant, splice_region_variant	20/21
RS1	XM_047442337.1	c.-209C>T		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000379989.6	c.2980G>A	p.Gly994Arg	missense_variant, splice_region_variant	21/22	1
CDKL5	ENST00000379996.7	c.2980G>A	p.Gly994Arg	missense_variant, splice_region_variant	20/21	1
RS1	ENST00000379984.4	c.185-3260C>T		intron_variant		1	NM_000330.4	P1
CDKL5	ENST00000673617.1	n.252G>A		splice_region_variant, non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000547 AC: 1 AN: 182807 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 67319

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 18 AN: 1097473 Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 3 AN XY: 362841

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000264

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Epileptic encephalopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neurogenetics Laboratory - MEYER, AOU Meyer

Nov 16, 2016

- -

CDKL5 disorder Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Feb 20, 2023

RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2980G>A (p.Gly994Arg) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3260C>T) is present in 0 female/1 male individual in gnomAD v2.1.1 (0.001227%) (not sufficient to meet BS1 criteria). Computational analysis prediction tools suggest that the p.Gly994Arg variant in CDKL5 does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Gly994Arg variant in CDKL5 is observed in at least 1 unaffected individual (PMID 29264392) (BS2_Supporting). In summary, the p.Gly994Arg in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2_Supporting, BP4). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	20
Dann	Benign	0.95
DEOGEN2	Benign	0.025	T;T
FATHMM_MKL	Benign	0.020	N
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.086
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0040	B;B
Vest4		0.35
MutPred		0.20		Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);
MVP		0.25
MPC		1.2
ClinPred		0.32	T
GERP RS		-0.19
Varity_R		0.17
gMVP		0.046

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
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: rs866859766; hg19: chrX-18668712;