X-18613214-C-G

Variant names:

• chrX-18613214-C-G
• rs747554139
• NM_001323289.2:c.2215C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001323289.2(CDKL5):​c.2215C>G​(p.Leu739Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000904 in 110,665 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L739L) has been classified as Likely benign. The gene CDKL5 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0650
• 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]

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

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045918316).

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.2215C>G	p.Leu739Val	missense	Exon 15 of 18	NP_001310218.1	O76039-2
	CDKL5	NM_001037343.2		c.2215C>G	p.Leu739Val	missense	Exon 16 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2215C>G	p.Leu739Val	missense	Exon 15 of 21	NP_003150.1	O76039-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000623535.2	TSL:1 MANE Select	c.2215C>G	p.Leu739Val	missense	Exon 15 of 18	ENSP00000485244.1	O76039-2
	CDKL5	ENST00000379989.6	TSL:1	c.2215C>G	p.Leu739Val	missense	Exon 16 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2215C>G	p.Leu739Val	missense	Exon 15 of 21	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.00000904 AC: 1 AN: 110628 Hom.: 0 Cov.: 22

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: 0.000384

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183443 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.22e-7 AC: 1 AN: 1084991 Hom.: 0 Cov.: 29 AF XY: 0.00000284 AC XY: 1 AN XY: 352223

African (AFR) AF: 0.00 AC: 0 AN: 26113

American (AMR) AF: 0.00 AC: 0 AN: 34897

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19008

East Asian (EAS) AF: 0.00 AC: 0 AN: 29493

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39599

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4063

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 832576

Other (OTH) AF: 0.00 AC: 0 AN: 45370

GnomAD4 genome AF: 0.00000904 AC: 1 AN: 110665 Hom.: 0 Cov.: 22 AF XY: 0.0000304 AC XY: 1 AN XY: 32939

African (AFR) AF: 0.00 AC: 0 AN: 30448

American (AMR) AF: 0.00 AC: 0 AN: 10373

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2632

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.000387 AC: 1 AN: 2587

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52965

Other (OTH) AF: 0.00 AC: 0 AN: 1499

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.065
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.11
Sift	Benign	0.27	T
Sift4G	Benign	0.36	T
Polyphen		0.21	B
Vest4		0.13
MutPred		0.084		Gain of sheet (P = 0.0827)
MVP		0.57
MPC		0.58
ClinPred		0.17	T
GERP RS		4.2
Varity_R		0.14
gMVP		0.13
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: rs747554139; hg19: chrX-18631334; COSMIC: COSV105324255;