rs368344738

Variant names:

• chrX-18650453-G-A
• rs368344738
• ENST00000379989.6:c.2841G>A
• CDKL5 p.Pro947Pro

Your query was ambiguous. Multiple possible variants found:

• chrX-18650453-G-A
• chrX-18650453-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_003159.3(CDKL5):​c.2841G>A​(p.Pro947Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,210,173 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). The gene CDKL5 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 0 hem.)
• Consequence: CDKL5 NM_003159.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.436
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-18650453-G-A is Benign according to our data. Variant chrX-18650453-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 533395.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.436 with no splicing effect.

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.185-3121C>T		intron	N/A	NP_000321.1	O15537
	CDKL5	NM_001037343.2		c.2841G>A	p.Pro947Pro	synonymous	Exon 21 of 22	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2841G>A	p.Pro947Pro	synonymous	Exon 20 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.2841G>A	p.Pro947Pro	synonymous	Exon 21 of 22	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2841G>A	p.Pro947Pro	synonymous	Exon 20 of 21	ENSP00000369332.3	O76039-1
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.185-3121C>T		intron	N/A	ENSP00000369320.3	O15537

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112069 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: 0.00000545 AC: 1 AN: 183499 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1098104 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363458

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

African (AFR) AF: 0.0000379 AC: 1 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 842010

Other (OTH) AF: 0.00 AC: 0 AN: 46094

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000396870), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112069 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34241

African (AFR) AF: 0.00 AC: 0 AN: 30840

American (AMR) AF: 0.00 AC: 0 AN: 10597

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3562

South Asian (SAS) AF: 0.00 AC: 0 AN: 2717

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53147

Other (OTH) AF: 0.00 AC: 0 AN: 1510

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 2;CN128785:Angelman syndrome-like (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.38
DANN	Benign	0.62
PhyloP100		-0.44

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: rs368344738;

hg19: chrX-18668573;

COSMIC: COSV66106996;