X-18604018-G-C

Position:

• chrX-18604018-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001323289.2(CDKL5):​c.1094G>C​(p.Ser365Thr) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.77

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1970276).
• BP6: Variant X-18604018-G-C is Benign according to our data. Variant chrX-18604018-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 548569.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.1094G>C	p.Ser365Thr	missense_variant	12/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.1094G>C	p.Ser365Thr	missense_variant	13/22		NP_001032420.1
CDKL5	NM_003159.3	c.1094G>C	p.Ser365Thr	missense_variant	12/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.1094G>C	p.Ser365Thr	missense_variant	12/18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.028	T;T;.;T;.;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	.;T;T;T;T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.2	L;.;.;L;.;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.13	N;.;.;N;.;.
REVEL	Benign	0.060
Sift	Benign	0.063	T;.;.;T;.;.
Sift4G	Benign	0.15	T;.;.;T;T;T
Polyphen		0.087	B;.;.;B;.;.
Vest4		0.18
MutPred		0.23		Loss of disorder (P = 0.1245);Loss of disorder (P = 0.1245);Loss of disorder (P = 0.1245);Loss of disorder (P = 0.1245);Loss of disorder (P = 0.1245);Loss of disorder (P = 0.1245);
MVP		0.76
MPC		0.40
ClinPred		0.63	D
GERP RS		5.2
Varity_R		0.28
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs1279388510; hg19: chrX-18622138;