rs748459878

Variant names:

• chrX-18613242-A-C
• rs748459878
• NM_001323289.2:c.2243A>C

Your query was ambiguous. Multiple possible variants found:

• chrX-18613242-A-C
• chrX-18613242-A-G

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.2243A>C​(p.Asn748Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N748S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.91

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=0.25938752).
• BP6: Variant X-18613242-A-C is Benign according to our data. Variant chrX-18613242-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 657569.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.2243A>C	p.Asn748Thr	missense_variant	Exon 15 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.2243A>C	p.Asn748Thr	missense_variant	Exon 16 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.2243A>C	p.Asn748Thr	missense_variant	Exon 15 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.2243A>C	p.Asn748Thr	missense_variant	Exon 15 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Benign:1

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T;T;T;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	.;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.9	L;.;L;.;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N;.;N;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D;.;D;.;.
Sift4G	Benign	0.26	T;.;T;T;T
Polyphen		0.97	D;.;D;.;.
Vest4		0.39
MutPred		0.082		Gain of glycosylation at N748 (P = 0.0206);Gain of glycosylation at N748 (P = 0.0206);Gain of glycosylation at N748 (P = 0.0206);Gain of glycosylation at N748 (P = 0.0206);Gain of glycosylation at N748 (P = 0.0206);
MVP		0.82
MPC		0.62
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.57
gMVP		0.19

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: rs748459878; hg19: chrX-18631362;