X-18650553-C-T

Variant names:

• chrX-18650553-C-T
• rs374054249
• ENST00000379989.6:c.2941C>T
• CDKL5 p.Arg981*

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

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.2941C>T (p.Arg981Ter) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3221G>A) is present in 14 XX and 7 XY individuals in gnomAD v4 (0.0043%) (not sufficient to meet BS1 criteria). The p.Arg981Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (not sufficient to meet PVS1 criteria). Additionally, the p.Arg981Ter variant is observed in at least 6 unaffected individuals (internal database - Invitae, internal database - GeneDx) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Arg981Ter variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA412373781/MONDO:0100039/034

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000019 (0 hom. 7 hem.)
• Consequence: CDKL5 NM_003159.3 stop_gained
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:2
• Conservation: PhyloP100: -0.0770
• 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: Labcorp Genetics (formerly Invitae), Myriad Women's Health, Orphanet, Ambry Genetics, PanelApp Australia, ClinGen

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 -4 ACMG points.

• 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.185-3221G>A		intron	N/A	NP_000321.1	O15537
	CDKL5	NM_001037343.2		c.2941C>T	p.Arg981*	stop_gained	Exon 21 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2941C>T	p.Arg981*	stop_gained	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.2941C>T	p.Arg981*	stop_gained	Exon 21 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2941C>T	p.Arg981*	stop_gained	Exon 20 of 21	ENSP00000369332.3	O76039-1
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.185-3221G>A		intron	N/A	ENSP00000369320.3	O15537

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183367 AF XY: 0.0000147

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000191 AC: 21 AN: 1098155 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 7 AN XY: 363509

African (AFR) AF: 0.0000379 AC: 1 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

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

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

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000190 AC: 16 AN: 842068

Other (OTH) AF: 0.0000434 AC: 2 AN: 46094

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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 (1)
-	-	1	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Benign	0.92
FATHMM_MKL	Benign	0.0016	N
PhyloP100		-0.077
Mutation Taster		=115/85	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs374054249;

hg19: chrX-18668673;