ENST00000379989.6:c.2995G>A

Variant names:

• chrX-18653446-G-A
• rs35693326
• ENST00000379989.6:c.2995G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000379989.6(CDKL5):​c.2995G>A​(p.Val999Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00565 in 1,209,251 control chromosomes in the GnomAD database, including 257 homozygotes. There are 1,817 hemizygotes in GnomAD. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V999V) has been classified as Likely benign. The gene CDKL5 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.029 (140 hom., 800 hem., cov: 23)
  • Exomes 𝑓: 0.0033 (117 hom. 1017 hem.)
• Consequence: CDKL5 ENST00000379989.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• 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: Myriad Women’s Health, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet

ACMG classification

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002029866).
• BP6: Variant X-18653446-G-A is Benign according to our data. Variant chrX-18653446-G-A is described in ClinVar as Benign. ClinVar VariationId is 94110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0971 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000379989.6. 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>T		intron	N/A	NP_000321.1	O15537
	CDKL5	NM_001037343.2		c.2995G>A	p.Val999Met	missense	Exon 22 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2995G>A	p.Val999Met	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>A	p.Val999Met	missense	Exon 22 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2995G>A	p.Val999Met	missense	Exon 21 of 21	ENSP00000369332.3	O76039-1
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.184+3207C>T		intron	N/A	ENSP00000369320.3	O15537

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 3203 AN: 111478 Hom.: 140 Cov.: 23

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00888

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.000320

Gnomad OTH AF: 0.0214

GnomAD2 exomes AF: 0.00851 AC: 1548 AN: 181957 AF XY: 0.00583

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.00494

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00330 AC: 3622 AN: 1097724 Hom.: 117 Cov.: 31 AF XY: 0.00280 AC XY: 1017 AN XY: 363130

African (AFR) AF: 0.108 AC: 2842 AN: 26390

American (AMR) AF: 0.00552 AC: 194 AN: 35174

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

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

South Asian (SAS) AF: 0.000629 AC: 34 AN: 54077

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

Middle Eastern (MID) AF: 0.00642 AC: 26 AN: 4051

European-Non Finnish (NFE) AF: 0.000227 AC: 191 AN: 841972

Other (OTH) AF: 0.00727 AC: 335 AN: 46062

GnomAD4 genome AF: 0.0288 AC: 3207 AN: 111527 Hom.: 140 Cov.: 23 AF XY: 0.0237 AC XY: 800 AN XY: 33733

African (AFR) AF: 0.100 AC: 3061 AN: 30594

American (AMR) AF: 0.00886 AC: 93 AN: 10491

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3517

South Asian (SAS) AF: 0.00112 AC: 3 AN: 2685

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

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.000320 AC: 17 AN: 53155

Other (OTH) AF: 0.0212 AC: 32 AN: 1511

Alfa AF: 0.0102 Hom.: 407

Bravo AF: 0.0332

ESP6500AA AF: 0.106 AC: 408

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.00973 AC: 1181

EpiCase AF: 0.000491

EpiControl AF: 0.000715

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	not provided (2)
-	-	1	CDKL5 disorder (1)
-	-	1	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	West syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.52
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.034
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.28	B
Vest4		0.093
MVP		0.28
MPC		0.78
ClinPred		0.037	T
GERP RS		-0.0082
Varity_R		0.085
gMVP		0.035
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35693326; hg19: chrX-18671566;