rs951430019

Positions:

chrX-18646076-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000379984.4(RS1):c.326+1115G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000455 in 1,210,029 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 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 0.000045 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000046 ( 0 hom. 13 hem. )

Consequence

RS1
ENST00000379984.4 intron

Scores

Clinical Significance

Likely benign reviewed by expert panel B:3

Conservation

PhyloP100: -0.347

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035787225).

BP6

Variant X-18646076-C-T is Benign according to our data. Variant chrX-18646076-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 464817.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RS1	NM_000330.4 linkuse as main transcript	c.326+1115G>A		intron_variant		ENST00000379984.4	NP_000321.1
CDKL5	NM_001037343.2 linkuse as main transcript	c.2783C>T	p.Thr928Met	missense_variant	20/22		NP_001032420.1
CDKL5	NM_003159.3 linkuse as main transcript	c.2783C>T	p.Thr928Met	missense_variant	19/21		NP_003150.1
RS1	XM_047442337.1 linkuse as main transcript	c.230+1115G>A		intron_variant			XP_047298293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000379989.6 linkuse as main transcript	c.2783C>T	p.Thr928Met	missense_variant	20/22	1		ENSP00000369325		O76039-1
CDKL5	ENST00000379996.7 linkuse as main transcript	c.2783C>T	p.Thr928Met	missense_variant	19/21	1		ENSP00000369332		O76039-1
RS1	ENST00000379984.4 linkuse as main transcript	c.326+1115G>A		intron_variant		1	NM_000330.4	ENSP00000369320	P1
RS1	ENST00000476595.1 linkuse as main transcript	n.817+1115G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000447

AC:

AN:

111856

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

34046

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

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

181634

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67396

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000993

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000523

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000447

AC:

AN:

111856

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

34046

show subpopulations

Gnomad4 AFR

AF:

0.000163

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2016

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

Likely benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Feb 20, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.1

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

MutationTaster

Benign

1.0

N;N;N

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over