chrX-18628547-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001323289.2(CDKL5):c.2673G>A(p.Gln891Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000958 in 1,210,338 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 40 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000096 ( 0 hom. 38 hem. )

Consequence

CDKL5
NM_001323289.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.15

Publications

1 publications found

Variant links:

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]

CDKL5 Gene-Disease associations (from GenCC):

CDKL5 disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 2
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
atypical Rett syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
precocious puberty
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

CDKL5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant X-18628547-G-A is Benign according to our data. Variant chrX-18628547-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 189534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628547-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 189534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628547-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 189534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628547-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 189534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628547-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 189534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628547-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 189534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18628547-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 189534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.15 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000981 (11/112131) while in subpopulation AMR AF = 0.000188 (2/10623). AF 95% confidence interval is 0.0000744. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 11 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKL5	NM_001323289.2 link	c.2673G>A	p.Gln891Gln	synonymous_variant	Exon 18 of 18	ENST00000623535.2	NP_001310218.1	O76039-2
CDKL5	NM_001037343.2 link	c.2673G>A	p.Gln891Gln	synonymous_variant	Exon 19 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.2673G>A	p.Gln891Gln	synonymous_variant	Exon 18 of 21		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDKL5	ENST00000623535.2 link	c.2673G>A	p.Gln891Gln	synonymous_variant	Exon 18 of 18	1	NM_001323289.2	ENSP00000485244.1	O76039-2
CDKL5	ENST00000379989.6 link	c.2673G>A	p.Gln891Gln	synonymous_variant	Exon 19 of 22	1		ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7 link	c.2673G>A	p.Gln891Gln	synonymous_variant	Exon 18 of 21	1		ENSP00000369332.3	O76039-1
CDKL5	ENST00000674046.1 link	c.2796G>A	p.Gln932Gln	synonymous_variant	Exon 19 of 19			ENSP00000501174.1	A0A669KBC2

Frequencies

GnomAD3 genomes

AF:

0.0000981

AC:

AN:

112131

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

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:

0.000150

Gnomad OTH

AF:

0.000668

GnomAD2 exomes

AF:

0.0000983

AC:

AN:

183118

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000401

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000735

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000956

AC:

105

AN:

1098207

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

363561

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.000341

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54145

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000107

AC:

AN:

842102

Other (OTH)

AF:

0.0000651

AC:

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000981

AC:

AN:

112131

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

34303

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30905

American (AMR)

AF:

0.000188

AC:

AN:

10623

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3547

South Asian (SAS)

AF:

0.00

AC:

AN:

2713

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6091

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.000150

AC:

AN:

53189

Other (OTH)

AF:

0.000668

AC:

AN:

1496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.000113

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 15, 2014

RettBASE

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Apr 28, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 14, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CDKL5 disorder

Benign:1

Jul 02, 2024

Centre for Population Genomics, CPG

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD v3 is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1). -

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

Benign:1

Nov 19, 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

BayesDel_noAF

Benign

-0.56

CADD

Benign

4.6

(source)

DANN

Benign

0.48

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over