X-18653446-G-T

Variant names:

• chrX-18653446-G-T
• rs35693326
• ENST00000379989.6:c.2995G>T
• CDKL5 p.Val999Leu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003159.3(CDKL5):​c.2995G>T​(p.Val999Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,209,217 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. 15/21 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. V999M) has been classified as Benign. The gene CDKL5 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: CDKL5 NM_003159.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.515
• Publications: 13 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, Myriad Women's Health, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for CDKL5 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09035358).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003159.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RS1	NM_000330.4	MANE Select	c.184+3207C>A		intron	N/A	NP_000321.1	O15537
	CDKL5	NM_001037343.2		c.2995G>T	p.Val999Leu	missense	Exon 22 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2995G>T	p.Val999Leu	missense	Exon 21 of 21	NP_003150.1	O76039-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000379989.6	TSL:1	c.2995G>T	p.Val999Leu	missense	Exon 22 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2995G>T	p.Val999Leu	missense	Exon 21 of 21	ENSP00000369332.3	O76039-1
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.184+3207C>A		intron	N/A	ENSP00000369320.3	O15537

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111490 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.00000550 AC: 1 AN: 181957 AF XY: 0.0000150

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097727 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363133

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26391

American (AMR) AF: 0.00 AC: 0 AN: 35175

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 54077

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40425

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4051

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841973

Other (OTH) AF: 0.00 AC: 0 AN: 46062

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111490 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33678

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30539

American (AMR) AF: 0.00 AC: 0 AN: 10478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.00 AC: 0 AN: 2696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53162

Other (OTH) AF: 0.00 AC: 0 AN: 1492

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 407

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.8
DANN	Benign	0.90
DEOGEN2	Benign	0.032	T
FATHMM_MKL	Benign	0.0076	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.52
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.11
gMVP		0.028
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs35693326;

hg19: chrX-18671566;