chrX-18604306-A-C

Variant names:

• chrX-18604306-A-C
• NM_001323289.2:c.1382A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001323289.2(CDKL5):​c.1382A>C​(p.Asn461Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,707 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04

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=0.058787197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2	c.1382A>C	p.Asn461Thr	missense_variant	Exon 12 of 18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.1382A>C	p.Asn461Thr	missense_variant	Exon 13 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.1382A>C	p.Asn461Thr	missense_variant	Exon 12 of 21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.1382A>C	p.Asn461Thr	missense_variant	Exon 12 of 18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097707 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363113

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.031	T;T;.;T;.;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	.;T;T;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.059	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;N;.;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.2	N;.;.;N;.;.
REVEL	Benign	0.11
Sift	Benign	0.10	T;.;.;T;.;.
Sift4G	Benign	0.33	T;.;.;T;T;T
Polyphen		0.0	B;.;.;B;.;.
Vest4		0.12
MutPred		0.11		Gain of glycosylation at N461 (P = 0.0158);Gain of glycosylation at N461 (P = 0.0158);Gain of glycosylation at N461 (P = 0.0158);Gain of glycosylation at N461 (P = 0.0158);Gain of glycosylation at N461 (P = 0.0158);Gain of glycosylation at N461 (P = 0.0158);
MVP		0.53
MPC		0.35
ClinPred		0.093	T
GERP RS		3.0
Varity_R		0.078
gMVP		0.046

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-18622426;