NM_001323289.2:c.194G>A

Variant names:

• chrX-18575402-G-A
• rs267608436
• NM_001323289.2:c.194G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP5 BS2

This summary comes from the ClinGen Evidence Repository: The p.Arg65Gln variant in CDKL5 is present in 2 female and 1 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Arg65Gln variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Arg65Gln variant is found in 2 patients with an alternate molecular basis of disease (internal database) (BP5). In summary, the p.Arg65Gln variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA170462/MONDO:0100039/034

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 8 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Likely benign reviewed by expert panel B:6
• Conservation: PhyloP100: 10.0
• Publications: 6 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: Likely_benign. The variant received -5 ACMG points.

• BP5: 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_001323289.2. 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
	CDKL5	NM_001323289.2	MANE Select	c.194G>A	p.Arg65Gln	missense	Exon 5 of 18	NP_001310218.1
	CDKL5	NM_001037343.2		c.194G>A	p.Arg65Gln	missense	Exon 6 of 22	NP_001032420.1
	CDKL5	NM_003159.3		c.194G>A	p.Arg65Gln	missense	Exon 5 of 21	NP_003150.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.194G>A	p.Arg65Gln	missense	Exon 5 of 18	ENSP00000485244.1
	CDKL5	ENST00000379989.6	TSL:1	c.194G>A	p.Arg65Gln	missense	Exon 6 of 22	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.194G>A	p.Arg65Gln	missense	Exon 5 of 21	ENSP00000369332.3

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111779 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: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 182997 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 18 AN: 1093207 Hom.: 0 Cov.: 28 AF XY: 0.0000223 AC XY: 8 AN XY: 358913

African (AFR) AF: 0.00 AC: 0 AN: 26282

American (AMR) AF: 0.0000284 AC: 1 AN: 35165

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19334

East Asian (EAS) AF: 0.00 AC: 0 AN: 30154

South Asian (SAS) AF: 0.00 AC: 0 AN: 54021

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40511

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.0000203 AC: 17 AN: 837697

Other (OTH) AF: 0.00 AC: 0 AN: 45929

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111779 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 34005

African (AFR) AF: 0.00 AC: 0 AN: 30776

American (AMR) AF: 0.00 AC: 0 AN: 10514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3556

South Asian (SAS) AF: 0.00 AC: 0 AN: 2686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6001

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

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53161

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	CDKL5 disorder (2)
-	-	1	CDKL5-related 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.41	N
PhyloP100		10
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.68
Sift	Benign	0.031	D
Sift4G	Benign	0.078	T
Polyphen		1.0	D
Vest4		0.91
MutPred		0.86		Loss of MoRF binding (P = 0.0201)
MVP		0.92
MPC		2.4
ClinPred		0.80	D
GERP RS		5.7
Varity_R		0.86
gMVP		0.93
Mutation Taster		=67/33	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: rs267608436; hg19: chrX-18593522; COSMIC: COSV66111634; COSMIC: COSV66111634;