rs143243059

Variant names:

• chrX-18650545-T-G
• rs143243059
• ENST00000379989.6:c.2933T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1 BP4

This summary comes from the ClinGen Evidence Repository: 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 allele frequency of the c.2933T>G (p.Leu978Arg) variant in the CDKL5 transcript (NM_003159.2) (RS1 c.185-3213A>C) is 0.01184% in the European (non-Finnish) sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational analysis prediction tools suggest that the p.Leu978Arg variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Leu978Arg variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10360748/MONDO:0100039/016

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.000097 (0 hom. 24 hem.)
• Consequence: CDKL5 NM_003159.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:3
• Conservation: PhyloP100: 0.361
• Publications: 1 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]

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]

RS1 Gene-Disease associations (from GenCC):

• retinoschisis

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• X-linked retinoschisis

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003159.3. 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
	RS1	NM_000330.4	MANE Select	c.185-3213A>C		intron	N/A	NP_000321.1	O15537
	CDKL5	NM_001037343.2		c.2933T>G	p.Leu978Arg	missense	Exon 21 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2933T>G	p.Leu978Arg	missense	Exon 20 of 21	NP_003150.1	O76039-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000379989.6	TSL:1	c.2933T>G	p.Leu978Arg	missense	Exon 21 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2933T>G	p.Leu978Arg	missense	Exon 20 of 21	ENSP00000369332.3	O76039-1
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.185-3213A>C		intron	N/A	ENSP00000369320.3	O15537

Frequencies

GnomAD3 genomes AF: 0.0000799 AC: 9 AN: 112571 Hom.: 0 Cov.: 24

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000169

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 183424 AF XY: 0.0000442

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000974 AC: 107 AN: 1098175 Hom.: 0 Cov.: 30 AF XY: 0.0000660 AC XY: 24 AN XY: 363531

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.000115 AC: 97 AN: 842075

Other (OTH) AF: 0.000217 AC: 10 AN: 46096

GnomAD4 genome AF: 0.0000799 AC: 9 AN: 112571 Hom.: 0 Cov.: 24 AF XY: 0.0000576 AC XY: 2 AN XY: 34717

African (AFR) AF: 0.00 AC: 0 AN: 30974

American (AMR) AF: 0.00 AC: 0 AN: 10684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3592

South Asian (SAS) AF: 0.00 AC: 0 AN: 2730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000169 AC: 9 AN: 53289

Other (OTH) AF: 0.00 AC: 0 AN: 1523

Alfa AF: 0.000174 Hom.: 1

Bravo AF: 0.0000529

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	CDKL5 disorder (1)
-	-	1	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.029	T
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.37	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.36
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.52
MVP		0.36
MPC		1.1
ClinPred		0.058	T
GERP RS		-3.2
Varity_R		0.22
gMVP		0.50
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs143243059; hg19: chrX-18668665;