rs587783158

Variant names:

• chrX-18628470-C-G
• rs587783158
• NM_001323289.2:c.2596C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-18628470-C-G
• chrX-18628470-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001323289.2(CDKL5):​c.2596C>G​(p.Gln866Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.19
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14655936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2596C>G	p.Gln866Glu	missense_variant	Exon 18 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2596C>G	p.Gln866Glu	missense_variant	Exon 19 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.2596C>G	p.Gln866Glu	missense_variant	Exon 18 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2596C>G	p.Gln866Glu	missense_variant	Exon 18 of 18	1	NM_001323289.2	ENSP00000485244.1
CDKL5	ENST00000379989.6	c.2596C>G	p.Gln866Glu	missense_variant	Exon 19 of 22	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2596C>G	p.Gln866Glu	missense_variant	Exon 18 of 21	1		ENSP00000369332.3
CDKL5	ENST00000674046.1	c.2719C>G	p.Gln907Glu	missense_variant	Exon 19 of 19			ENSP00000501174.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDKL5 c.2596C>G (p.Gln866Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 183492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2596C>G in individuals affected with Early Infantile Epileptic Encephalopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.023	T;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	.;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.1	L;L;L
PhyloP100		4.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.58	N;N;.
REVEL	Benign	0.10
Sift	Benign	0.068	T;T;.
Sift4G	Benign	0.096	T;T;T
Polyphen		0.19	B;B;.
Vest4		0.17
MutPred		0.13		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);
MVP		0.68
MPC		0.39
ClinPred		0.54	D
GERP RS		5.7
Varity_R		0.24
gMVP		0.12
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587783158; hg19: chrX-18646590;