rs267608664

Positions:

• chrX-18646060-C-A
• chrX-18646060-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

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. 13/19 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0485332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RS1	NM_000330.4	c.326+1131G>T		intron_variant		ENST00000379984.4
CDKL5	NM_001037343.2	c.2767C>A	p.Arg923Ser	missense_variant	20/22
CDKL5	NM_003159.3	c.2767C>A	p.Arg923Ser	missense_variant	19/21
RS1	XM_047442337.1	c.230+1131G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000379989.6	c.2767C>A	p.Arg923Ser	missense_variant	20/22	1
CDKL5	ENST00000379996.7	c.2767C>A	p.Arg923Ser	missense_variant	19/21	1
RS1	ENST00000379984.4	c.326+1131G>T		intron_variant		1	NM_000330.4	P1
RS1	ENST00000476595.1	n.817+1131G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000220 AC: 4 AN: 181639 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67401

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 SAS 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: 4 AN: 1098199 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363555

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000114

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.14
DANN	Benign	0.97
DEOGEN2	Benign	0.026	T;T
FATHMM_MKL	Benign	0.00073	N
LIST_S2	Benign	0.43	.;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
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	T
GERP RS		0.69
Varity_R		0.14
gMVP		0.33

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: rs267608664; hg19: chrX-18664180;