rs587783403

Variant names:

• chrX-18650432-C-A
• rs587783403
• ENST00000379989.6:c.2820C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000379989.6(CDKL5):​c.2820C>A​(p.Asp940Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CDKL5 ENST00000379989.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.20
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043536246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4	c.185-3100G>T		intron_variant	Intron 3 of 5	ENST00000379984.4	NP_000321.1
CDKL5	NM_001037343.2	c.2820C>A	p.Asp940Glu	missense_variant	Exon 21 of 22		NP_001032420.1
CDKL5	NM_003159.3	c.2820C>A	p.Asp940Glu	missense_variant	Exon 20 of 21		NP_003150.1
RS1	XM_047442337.1	c.-49G>T		5_prime_UTR_variant	Exon 1 of 4		XP_047298293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.185-3100G>T		intron_variant	Intron 3 of 5	1	NM_000330.4	ENSP00000369320.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 2 Uncertain:1

Apr 05, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.31
DANN	Benign	0.96
DEOGEN2	Benign	0.017	T;T
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.31	.;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		-2.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.40	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.015	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;B
Vest4		0.078
MutPred		0.057		Gain of glycosylation at P941 (P = 0.1397);Gain of glycosylation at P941 (P = 0.1397);
MVP		0.26
MPC		0.59
ClinPred		0.073	T
GERP RS		-1.7
Varity_R		0.070
gMVP		0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587783403; hg19: chrX-18668552;