rs756986206

Variant names:

• chrX-18603926-T-C
• rs756986206
• NM_001323289.2:c.1002T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BS2_Supporting BA1

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Ala334= variant in CDKL5 is 0.07448% in South Asian 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.Ala334= variant is observed in at least 1 unaffected individual (Clinvar 210642) (BS2_supporting). The silent p.Ala334= variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Ala334= variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BA1, BA2_supporting, BP7). LINK:https://erepo.genome.network/evrepo/ui/classification/CA207213/MONDO:0100039/016

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (2 hom. 43 hem.)
• Consequence: CDKL5 NM_001323289.2 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:7
• Conservation: PhyloP100: 0.772
• 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]

CDKL5 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• 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_001323289.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	NM_001323289.2	MANE Select	c.1002T>C	p.Ala334Ala	synonymous	Exon 12 of 18	NP_001310218.1
	CDKL5	NM_001037343.2		c.1002T>C	p.Ala334Ala	synonymous	Exon 13 of 22	NP_001032420.1
	CDKL5	NM_003159.3		c.1002T>C	p.Ala334Ala	synonymous	Exon 12 of 21	NP_003150.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.1002T>C	p.Ala334Ala	synonymous	Exon 12 of 18	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.1002T>C	p.Ala334Ala	synonymous	Exon 13 of 22	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.1002T>C	p.Ala334Ala	synonymous	Exon 12 of 21	ENSP00000369332.3

Frequencies

GnomAD3 genomes AF: 0.0000447 AC: 5 AN: 111918 Hom.: 0 Cov.: 23

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: 0.0126

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000109 AC: 20 AN: 183298 AF XY: 0.000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 117 AN: 1097142 Hom.: 2 Cov.: 31 AF XY: 0.000119 AC XY: 43 AN XY: 362516

African (AFR) AF: 0.000227 AC: 6 AN: 26379

American (AMR) AF: 0.0000852 AC: 3 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.000998 AC: 54 AN: 54126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00629 AC: 26 AN: 4135

European-Non Finnish (NFE) AF: 0.0000214 AC: 18 AN: 841115

Other (OTH) AF: 0.000217 AC: 10 AN: 46065

GnomAD4 genome AF: 0.0000447 AC: 5 AN: 111970 Hom.: 0 Cov.: 23 AF XY: 0.0000879 AC XY: 3 AN XY: 34128

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30802

American (AMR) AF: 0.00 AC: 0 AN: 10587

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.00 AC: 0 AN: 2662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6055

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 218

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53239

Other (OTH) AF: 0.00 AC: 0 AN: 1520

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000862 Hom.: 1

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	CDKL5 disorder (1)
-	-	1	CDKL5-related disorder (1)
-	-	1	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.1
DANN	Benign	0.65
PhyloP100		0.77
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: rs756986206; hg19: chrX-18622046;