rs139155110

Variant names:

• chrX-18653535-G-A
• rs139155110
• ENST00000379989.6:c.3084G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-18653535-G-A
• chrX-18653535-G-C
• chrX-18653535-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS2 BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Thr1028= variant in CDKL5 is 2.6% in Ashkenazi Jewish 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.Thr1028= variant is observed in at least 2 unaffected individuals (internal database, BS2). In summary, the p.Thr1028= variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA147633/MONDO:0100039/016

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., 124 hem., cov: 23)
  • Exomes 𝑓: 0.0045 (18 hom. 1550 hem.)
• Consequence: CDKL5 NM_003159.3 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:14
• Conservation: PhyloP100: -0.408
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.184+3118C>T		intron	N/A	NP_000321.1	O15537
	CDKL5	NM_001037343.2		c.3084G>A	p.Thr1028Thr	synonymous	Exon 22 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.3084G>A	p.Thr1028Thr	synonymous	Exon 21 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.3084G>A	p.Thr1028Thr	synonymous	Exon 22 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.3084G>A	p.Thr1028Thr	synonymous	Exon 21 of 21	ENSP00000369332.3	O76039-1
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.184+3118C>T		intron	N/A	ENSP00000369320.3	O15537

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 396 AN: 112477 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.000776

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00113

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.00438

Gnomad MID AF: 0.0252

Gnomad NFE AF: 0.00437

Gnomad OTH AF: 0.00528

GnomAD2 exomes AF: 0.00415 AC: 754 AN: 181578 AF XY: 0.00397

Gnomad AFR exome AF: 0.000846

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.00495

Gnomad OTH exome AF: 0.00622

GnomAD4 exome AF: 0.00447 AC: 4906 AN: 1097659 Hom.: 18 Cov.: 31 AF XY: 0.00427 AC XY: 1550 AN XY: 363033

African (AFR) AF: 0.000985 AC: 26 AN: 26390

American (AMR) AF: 0.00207 AC: 73 AN: 35182

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 519 AN: 19375

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30190

South Asian (SAS) AF: 0.00128 AC: 69 AN: 54053

European-Finnish (FIN) AF: 0.00382 AC: 154 AN: 40351

Middle Eastern (MID) AF: 0.00799 AC: 33 AN: 4128

European-Non Finnish (NFE) AF: 0.00450 AC: 3791 AN: 841915

Other (OTH) AF: 0.00521 AC: 240 AN: 46075

GnomAD4 genome AF: 0.00350 AC: 394 AN: 112530 Hom.: 2 Cov.: 23 AF XY: 0.00357 AC XY: 124 AN XY: 34692

African (AFR) AF: 0.000774 AC: 24 AN: 31003

American (AMR) AF: 0.00113 AC: 12 AN: 10638

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 78 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.00290 AC: 8 AN: 2761

European-Finnish (FIN) AF: 0.00438 AC: 27 AN: 6162

Middle Eastern (MID) AF: 0.0275 AC: 6 AN: 218

European-Non Finnish (NFE) AF: 0.00433 AC: 231 AN: 53308

Other (OTH) AF: 0.00522 AC: 8 AN: 1534

Alfa AF: 0.00629 Hom.: 46

Bravo AF: 0.00330

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	CDKL5 disorder (2)
-	-	2	Developmental and epileptic encephalopathy, 2 (2)
-	1	1	not provided (2)
-	-	1	CDKL5-related disorder (1)
-	-	1	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)
-	-	1	History of neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.16
DANN	Benign	0.56
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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: rs139155110; hg19: chrX-18671655; COSMIC: COSV66105898; COSMIC: COSV66105898;