rs921600020

Positions:

• chrX-18604122-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_001323289.2(CDKL5):​c.1198A>C​(p.Asn400His) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,098,196 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: CDKL5 NM_001323289.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.92

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37612605).
• BP6: Variant X-18604122-A-C is Benign according to our data. Variant chrX-18604122-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 569644.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.1198A>C	p.Asn400His	missense_variant	12/18	ENST00000623535.2	NP_001310218.1
CDKL5	NM_001037343.2	c.1198A>C	p.Asn400His	missense_variant	13/22		NP_001032420.1
CDKL5	NM_003159.3	c.1198A>C	p.Asn400His	missense_variant	12/21		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000623535.2	c.1198A>C	p.Asn400His	missense_variant	12/18	1	NM_001323289.2	ENSP00000485244.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363556

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: 0.00

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T;T;.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.38	T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.0	M;.;.;M;.;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.0	N;.;.;N;.;.
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;.;.;D;.;.
Sift4G	Uncertain	0.048	D;.;.;D;D;T
Polyphen		1.0	D;.;.;D;.;.
Vest4		0.74
MutPred		0.16		Loss of stability (P = 0.1219);Loss of stability (P = 0.1219);Loss of stability (P = 0.1219);Loss of stability (P = 0.1219);Loss of stability (P = 0.1219);Loss of stability (P = 0.1219);
MVP		0.88
MPC		0.87
ClinPred		0.89	D
GERP RS		6.1
Varity_R		0.58
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: rs921600020; hg19: chrX-18622242;