rs35693326

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-18653446-G-A
• chrX-18653446-G-T

Variant summary

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

The NM_003159.3(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.

• Frequency:
  • Genomes: 𝑓 0.029 (140 hom., 800 hem., cov: 23)
  • Exomes 𝑓: 0.0033 (117 hom. 1017 hem.)
• Consequence: CDKL5 NM_003159.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• 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, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen

ACMG classification

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: 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>T		intron	N/A	NP_000321.1
	CDKL5	NM_001037343.2		c.2995G>A	p.Val999Met	missense	Exon 22 of 22	NP_001032420.1
	CDKL5	NM_003159.3		c.2995G>A	p.Val999Met	missense	Exon 21 of 21	NP_003150.1

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
	CDKL5	ENST00000379996.7	TSL:1	c.2995G>A	p.Val999Met	missense	Exon 21 of 21	ENSP00000369332.3
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.184+3207C>T		intron	N/A	ENSP00000369320.3

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 as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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;