rs587783162

chrX-18653459-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The ENST00000379989.6(CDKL5):c.3008T>C(p.Met1003Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,209,625 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 3 hem.)
• Consequence: CDKL5 ENST00000379989.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.375

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10630739).
• BP6: Variant X-18653459-T-C is Benign according to our data. Variant chrX-18653459-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 156695.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RS1	NM_000330.4	c.184+3194A>G		intron_variant		ENST00000379984.4
CDKL5	NM_001037343.2	c.3008T>C	p.Met1003Thr	missense_variant	22/22
CDKL5	NM_003159.3	c.3008T>C	p.Met1003Thr	missense_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKL5	ENST00000379989.6	c.3008T>C	p.Met1003Thr	missense_variant	22/22	1
CDKL5	ENST00000379996.7	c.3008T>C	p.Met1003Thr	missense_variant	21/21	1
RS1	ENST00000379984.4	c.184+3194A>G		intron_variant		1	NM_000330.4	P1
CDKL5	ENST00000673617.1	n.280T>C		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111650 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33814

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: 0.0000564

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1097975 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 3 AN XY: 363351

Gnomad4 AFR exome AF: 0.00

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: 0.0000107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111650 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33814

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: 0.0000564

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 19, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

CDKL5-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2022

The CDKL5 c.3008T>C variant is predicted to result in the amino acid substitution p.Met1003Thr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	1.1
Dann	Benign	0.56
DEOGEN2	Benign	0.031	T;T
FATHMM_MKL	Benign	0.030	N
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0010	B;B
Vest4		0.18
MutPred		0.37		Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);
MVP		0.18
MPC		0.42
ClinPred		0.090	T
GERP RS		0.45
Varity_R		0.45
gMVP		0.13

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: rs587783162; hg19: chrX-18671579;