chrX-18646060-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2BP4_StrongBS1

The ENST00000379989.6(CDKL5):c.2767C>A(p.Arg923Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,098,199 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R923C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000036 ( 0 hom. 1 hem. )

Consequence

CDKL5
ENST00000379989.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.230

Publications

3 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 links:

RS1 (HGNC:10457): (retinoschisin 1) This gene encodes an extracellular protein that plays a crucial role in the cellular organization of the retina. The encoded protein is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Mutations in this gene are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. [provided by RefSeq, Oct 2008]

RS1 Gene-Disease associations (from GenCC):

retinoschisis
Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
X-linked retinoschisis
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen

RS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0485332).

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000364 (4/1098199) while in subpopulation AMR AF = 0.000114 (4/35202). AF 95% confidence interval is 0.0000385. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RS1	NM_000330.4 link	c.326+1131G>T		intron_variant	Intron 4 of 5	ENST00000379984.4	NP_000321.1
CDKL5	NM_001037343.2 link	c.2767C>A	p.Arg923Ser	missense_variant	Exon 20 of 22		NP_001032420.1
CDKL5	NM_003159.3 link	c.2767C>A	p.Arg923Ser	missense_variant	Exon 19 of 21		NP_003150.1
RS1	XM_047442337.1 link	c.230+1131G>T		intron_variant	Intron 2 of 3		XP_047298293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CDKL5	ENST00000379989.6 link	c.2767C>A	p.Arg923Ser	missense_variant	Exon 20 of 22	1		ENSP00000369325.3
CDKL5	ENST00000379996.7 link	c.2767C>A	p.Arg923Ser	missense_variant	Exon 19 of 21	1		ENSP00000369332.3
RS1	ENST00000379984.4 link	c.326+1131G>T		intron_variant	Intron 4 of 5	1	NM_000330.4	ENSP00000369320.3
RS1	ENST00000476595.1 link	n.817+1131G>T		intron_variant	Intron 3 of 4	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000220

AC:

AN:

181639

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1098199

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363555

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.000114

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40525

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842101

Other (OTH)

AF:

0.00

AC:

AN:

46093

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.14

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.026

T;T

FATHMM_MKL

Benign

0.00073

LIST_S2

Benign

0.43

.;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;N

PhyloP100

-0.23

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.22

N;N

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.049

D;D

Polyphen

0.0

B;B

Vest4

0.094

MutPred

0.17

Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);

MVP

0.24

MPC

0.63

ClinPred

0.045

GERP RS

0.69

Varity_R

0.14

gMVP

0.33

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over