rs587783160

Variant names:

• chrX-18646032-G-C
• rs587783160
• ENST00000379989.6:c.2739G>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS2 BP4

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 non-coding 3' region of the main CDKL5 transcript (NM_ 001323289.2). The c.2739 G>C (p.Gln913His) variant in CDKL5 transcript (NM_003159.3) (RS1 c.326+1159 C>G) is observed in at least 2 unaffected individuals (GeneDx and Invitae internal databases) (BS2). Computational analysis prediction tools suggest that the c.2739 G>C variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the c.2739 G>C variant in the alternate CDKL5 transcript (NM_003159.3) is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA294768/MONDO:0100039/034

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000075 (0 hom. 26 hem.)
• Consequence: CDKL5 NM_003159.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:4
• Conservation: PhyloP100: 0.206

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: 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	c.326+1159C>G		intron_variant	Intron 4 of 5	ENST00000379984.4	NP_000321.1
CDKL5	NM_001037343.2	c.2739G>C	p.Gln913His	missense_variant	Exon 20 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.2739G>C	p.Gln913His	missense_variant	Exon 19 of 21		NP_003150.1
RS1	XM_047442337.1	c.230+1159C>G		intron_variant	Intron 2 of 3		XP_047298293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKL5	ENST00000379989.6	c.2739G>C	p.Gln913His	missense_variant	Exon 20 of 22	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2739G>C	p.Gln913His	missense_variant	Exon 19 of 21	1		ENSP00000369332.3
RS1	ENST00000379984.4	c.326+1159C>G		intron_variant	Intron 4 of 5	1	NM_000330.4	ENSP00000369320.3
RS1	ENST00000476595.1	n.817+1159C>G		intron_variant	Intron 3 of 4	1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111987 Hom.: 0 Cov.: 22 AF XY: 0.0000293 AC XY: 1 AN XY: 34159

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 181642 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67404

Gnomad AFR exome AF: 0.00

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: 0.0000250

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000747 AC: 82 AN: 1098221 Hom.: 0 Cov.: 31 AF XY: 0.0000715 AC XY: 26 AN XY: 363577

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000950

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111987 Hom.: 0 Cov.: 22 AF XY: 0.0000293 AC XY: 1 AN XY: 34159

Gnomad4 AFR AF: 0.00

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: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDKL5 disorder Benign:1

Apr 14, 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 non-coding 3' region of the main CDKL5 transcript (NM_ 001323289.2). The c.2739 G>C (p.Gln913His) variant in CDKL5 transcript (NM_003159.3) (RS1 c.326+1159 C>G) is observed in at least 2 unaffected individuals (GeneDx and Invitae internal databases) (BS2). Computational analysis prediction tools suggest that the c.2739 G>C variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the c.2739 G>C variant in the alternate CDKL5 transcript (NM_003159.3) is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4). -

not provided Benign:1

Apr 02, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDKL5-related disorder Benign:1

Sep 25, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like Benign:1

Oct 03, 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_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.0
DANN	Benign	0.91
DEOGEN2	Benign	0.018	T;T
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.31	.;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.31	N;N
REVEL	Benign	0.086
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.087	T;T
Polyphen		0.68	P;P
Vest4		0.063
MutPred		0.19		Gain of catalytic residue at Q913 (P = 0.0293);Gain of catalytic residue at Q913 (P = 0.0293);
MVP		0.49
MPC		0.45
ClinPred		0.070	T
GERP RS		1.0
Varity_R		0.098
gMVP		0.20

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: rs587783160; hg19: chrX-18664152;