rs267608478

Positions:

• chrX-18581972-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001323289.2(CDKL5):​c.463+22T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,044,977 control chromosomes in the GnomAD database, including 1 homozygotes. There are 124 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.00041 (1 hom. 117 hem.)
• Consequence: CDKL5 NM_001323289.2 intron
• Clinical Significance: Benign no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 0.128

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-18581972-T-C is Benign according to our data. Variant chrX-18581972-T-C is described in ClinVar as [Benign]. Clinvar id is 156089.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000251 (28/111597) while in subpopulation NFE AF= 0.000491 (26/52995). AF 95% confidence interval is 0.000343. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKL5	NM_001323289.2	c.463+22T>C		intron_variant		ENST00000623535.2
CDKL5	NM_001037343.2	c.463+22T>C		intron_variant
CDKL5	NM_003159.3	c.463+22T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000623535.2	c.463+22T>C		intron_variant		1	NM_001323289.2	P1

Frequencies

GnomAD3 genomes AF: 0.000251 AC: 28 AN: 111597 Hom.: 0 Cov.: 22 AF XY: 0.000207 AC XY: 7 AN XY: 33801

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000491

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000177 AC: 32 AN: 180301 Hom.: 0 AF XY: 0.000261 AC XY: 17 AN XY: 65141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000187

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000442

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000235

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000408 AC: 381 AN: 933380 Hom.: 1 Cov.: 17 AF XY: 0.000464 AC XY: 117 AN XY: 252226

Gnomad4 AFR exome AF: 0.0000860

Gnomad4 AMR exome AF: 0.000173

Gnomad4 ASJ exome AF: 0.0000550

Gnomad4 EAS exome AF: 0.0000341

Gnomad4 SAS exome AF: 0.000361

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000471

Gnomad4 OTH exome AF: 0.000591

GnomAD4 genome AF: 0.000251 AC: 28 AN: 111597 Hom.: 0 Cov.: 22 AF XY: 0.000207 AC XY: 7 AN XY: 33801

Gnomad4 AFR AF: 0.0000325

Gnomad4 AMR AF: 0.0000955

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000491

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 1

Bravo AF: 0.000242

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

curation

RettBASE

May 09, 2014

Reported in multiple unaffected family members -

not provided Other:1

not provided, flagged submission

literature only

RettBASE

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.82

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: rs267608478; hg19: chrX-18600092;