rs62643617

Positions:

• chrX-18625129-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001323289.2(CDKL5):​c.2378T>C​(p.Val793Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00001 in 1,095,234 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V793I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000010 (0 hom. 7 hem.)
• Consequence: CDKL5 NM_001323289.2 missense, splice_region
• Scores: Splicing: ADA: 0.09396
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.50

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23061052).
• BS2: High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.2378T>C	p.Val793Ala	missense_variant, splice_region_variant	17/18	ENST00000623535.2
CDKL5	NM_001037343.2	c.2378T>C	p.Val793Ala	missense_variant, splice_region_variant	18/22
CDKL5	NM_003159.3	c.2378T>C	p.Val793Ala	missense_variant, splice_region_variant	17/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.2378T>C	p.Val793Ala	missense_variant, splice_region_variant	17/18	1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000547 AC: 1 AN: 182886 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67408

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1095234 Hom.: 0 Cov.: 29 AF XY: 0.0000194 AC XY: 7 AN XY: 360830

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: 0.0000131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

curation

RettBASE

Mar 13, 2014

Not a conserved amino acid residue, sidechain effects likely to be conservative; no parental DNA available for testing; In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = possibly damaging, AlignGVGD = benign (C0) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T;T;T;.
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.5	L;.;L;L
MutationTaster	Benign	0.76	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.95	N;.;N;.
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D;.;D;.
Sift4G	Uncertain	0.0050	D;.;D;D
Polyphen		0.62	P;.;P;.
Vest4		0.27
MutPred		0.15		Loss of stability (P = 0.0313);Loss of stability (P = 0.0313);Loss of stability (P = 0.0313);Loss of stability (P = 0.0313);
MVP		0.77
MPC		0.42
ClinPred		0.31	T
GERP RS		6.0
Varity_R		0.26
gMVP		0.083

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.094
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.050		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: rs62643617; hg19: chrX-18643249;