chrX-18650469-G-T

Variant names:

• chrX-18650469-G-T
• rs767312604
• ENST00000379989.6:c.2857G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP5 BP4

This summary comes from the ClinGen Evidence Repository: RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2857G>T (p.Ala953Ser) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3137C>A) is present in 2 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Ala953Ser variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). Additionally, computational analysis prediction tools suggest that the p.Ala953Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ala953Ser variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BP5, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10360734/MONDO:0100039/034

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 7 hem.)
• Consequence: CDKL5 ENST00000379989.6 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 0.799
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RS1	NM_000330.4	MANE Select	c.185-3137C>A		intron	N/A	NP_000321.1
	CDKL5	NM_001037343.2		c.2857G>T	p.Ala953Ser	missense	Exon 21 of 22	NP_001032420.1
	CDKL5	NM_003159.3		c.2857G>T	p.Ala953Ser	missense	Exon 20 of 21	NP_003150.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKL5	ENST00000379989.6	TSL:1	c.2857G>T	p.Ala953Ser	missense	Exon 21 of 22	ENSP00000369325.3
	CDKL5	ENST00000379996.7	TSL:1	c.2857G>T	p.Ala953Ser	missense	Exon 20 of 21	ENSP00000369332.3
	RS1	ENST00000476595.1	TSL:1	n.69C>A		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183508 AF XY: 0.0000294

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: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000127 AC: 14 AN: 1098130 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 7 AN XY: 363490

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000166 AC: 14 AN: 842031

Other (OTH) AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1

Mar 14, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDKL5 disorder Benign:1

Feb 20, 2023

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2857G>T (p.Ala953Ser) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3137C>A) is present in 2 male individuals in gnomAD (0.002%) (not sufficient to meet BS1 criteria). The p.Ala953Ser variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). Additionally, computational analysis prediction tools suggest that the p.Ala953Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ala953Ser variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BP5, BP4).

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

Mar 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.80
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.093
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.61	T
Polyphen		0.018	B
Vest4		0.17
MutPred		0.21		Gain of phosphorylation at A953 (P = 0.0261)
MVP		0.33
MPC		0.54
ClinPred		0.067	T
GERP RS		0.54
Varity_R		0.095
gMVP		0.025
Mutation Taster		=97/3	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

Other links and lift over

dbSNP: rs767312604; hg19: chrX-18668589;