rs951430019

Variant names:

• chrX-18646076-C-T
• rs951430019
• ENST00000379989.6:c.2783C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS1 BS2_Supporting 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 c.2783C>T (p.Thr928Met) variant in CDKL5 transcript (NM_003159.2) (RS1 c.326+1115G>A) is 0.0188% in African sub population in gnomAD, which is high enough to be classified as likely benign 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.Thr928Met variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). Additionally, the p.Thr928Met variant is observed in at least 1 unaffected individual (PMID:31209962) (BS2_supporting). In summary, the p.Thr928Met variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4, BS2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA327012012/MONDO:0100039/034

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000046 (0 hom. 13 hem.)
• Consequence: CDKL5 NM_003159.3 missense
• Clinical Significance: Likely benign reviewed by expert panel B:3
• Conservation: PhyloP100: -0.347
• Publications: 0 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

Specifications for CDKL5 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -6 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.
• BS2: 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.326+1115G>A		intron	N/A	NP_000321.1	O15537
	CDKL5	NM_001037343.2		c.2783C>T	p.Thr928Met	missense	Exon 20 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2783C>T	p.Thr928Met	missense	Exon 19 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.2783C>T	p.Thr928Met	missense	Exon 20 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2783C>T	p.Thr928Met	missense	Exon 19 of 21	ENSP00000369332.3	O76039-1
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.326+1115G>A		intron	N/A	ENSP00000369320.3	O15537

Frequencies

GnomAD3 genomes AF: 0.0000447 AC: 5 AN: 111856 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000163

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 181634 AF XY: 0.0000148

Gnomad AFR exome AF: 0.0000760

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: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000455 AC: 50 AN: 1098173 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 13 AN XY: 363527

African (AFR) AF: 0.0000379 AC: 1 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.0000993 AC: 3 AN: 30201

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54147

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40528

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

European-Non Finnish (NFE) AF: 0.0000523 AC: 44 AN: 842077

Other (OTH) AF: 0.00 AC: 0 AN: 46094

GnomAD4 genome AF: 0.0000447 AC: 5 AN: 111856 Hom.: 0 Cov.: 22 AF XY: 0.0000587 AC XY: 2 AN XY: 34046

African (AFR) AF: 0.000163 AC: 5 AN: 30725

American (AMR) AF: 0.00 AC: 0 AN: 10548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3594

South Asian (SAS) AF: 0.00 AC: 0 AN: 2669

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6081

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53173

Other (OTH) AF: 0.00 AC: 0 AN: 1490

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

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	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
FATHMM_MKL	Benign	0.00048	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.35
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.11
Sift	Benign	0.26	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.0010	B
Vest4		0.077
MutPred		0.13		Gain of helix (P = 0.0199)
MVP		0.20
MPC		0.95
ClinPred		0.035	T
GERP RS		-3.8
Varity_R		0.015
gMVP		0.28
Mutation Taster		=100/0	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: rs951430019; hg19: chrX-18664196; COSMIC: COSV66107411;