ENST00000379989.6:c.2783C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS1BS2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2783C>T (p.Thr928Met) variant in CDKL5 transcript (NM_003159.2) (RS1 c.326+1115G>A) is 0.0188% in African sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational analysis prediction tools suggest that the p.Thr928Met variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). Additionally, the p.Thr928Met variant is observed in at least 1 unaffected individual (PMID:31209962) (BS2_supporting). In summary, the p.Thr928Met variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4, BS2_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA327012012/MONDO:0100039/034

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000046 ( 0 hom. 13 hem. )

Consequence

CDKL5
ENST00000379989.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel B:3

Conservation

PhyloP100: -0.347

Publications

0 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.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4 link	c.326+1115G>A		intron_variant	Intron 4 of 5	ENST00000379984.4	NP_000321.1	O15537
CDKL5	NM_001037343.2 link	c.2783C>T	p.Thr928Met	missense_variant	Exon 20 of 22		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.2783C>T	p.Thr928Met	missense_variant	Exon 19 of 21		NP_003150.1	O76039-1
RS1	XM_047442337.1 link	c.230+1115G>A		intron_variant	Intron 2 of 3		XP_047298293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDKL5	ENST00000379989.6 link	c.2783C>T	p.Thr928Met	missense_variant	Exon 20 of 22	1		ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7 link	c.2783C>T	p.Thr928Met	missense_variant	Exon 19 of 21	1		ENSP00000369332.3	O76039-1
RS1	ENST00000379984.4 link	c.326+1115G>A		intron_variant	Intron 4 of 5	1	NM_000330.4	ENSP00000369320.3	O15537
RS1	ENST00000476595.1 link	n.817+1115G>A		intron_variant	Intron 3 of 4	1

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

181634

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

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:

0.000221

GnomAD4 exome

AF:

0.0000455

AC:

AN:

1098173

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

363527

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.0000993

AC:

AN:

30201

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.0000247

AC:

AN:

40528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000523

AC:

AN:

842077

Other (OTH)

AF:

0.00

AC:

AN:

46094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.0000447

AC:

AN:

111856

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

34046

show subpopulations

African (AFR)

AF:

0.000163

AC:

AN:

30725

American (AMR)

AF:

0.00

AC:

AN:

10548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3594

South Asian (SAS)

AF:

0.00

AC:

AN:

2669

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6081

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53173

Other (OTH)

AF:

0.00

AC:

AN:

1490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Aug 29, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CDKL5 disorder

Benign:1

Feb 20, 2023

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2783C>T (p.Thr928Met) variant in CDKL5 transcript (NM_003159.2) (RS1 c.326+1115G>A) is 0.0188% in African sub population in gnomAD, which is high enough to be classified as likely benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Computational analysis prediction tools suggest that the p.Thr928Met variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). Additionally, the p.Thr928Met variant is observed in at least 1 unaffected individual (PMID: 31209962) (BS2_supporting). In summary, the p.Thr928Met variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BS1, BP4, BS2_supporting). -

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

Benign:1

Apr 12, 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

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.024

T;T

FATHMM_MKL

Benign

0.00048

LIST_S2

Benign

0.44

.;T

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

PhyloP100

-0.35

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.47

N;N

REVEL

Benign

0.11

Sift

Benign

0.26

T;T

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.0010

B;B

Vest4

0.077

MutPred

0.13

Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);

MVP

0.20

MPC

0.95

ClinPred

0.035

GERP RS

-3.8

Varity_R

0.015

gMVP

0.28

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