rs104894933

Variant names:

• chrX-18647296-C-A
• rs104894933
• NM_000330.4:c.221G>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000330.4(RS1):​c.221G>T​(p.Gly74Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,208,964 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G74G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: RS1 NM_000330.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.85
• Publications: 7 publications found

Genes affected

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]

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]

CDKL5 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000330.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 0.96911 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked retinoschisis, retinoschisis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-18647296-C-A is Pathogenic according to our data. Variant chrX-18647296-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 9890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000330.4. 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.221G>T	p.Gly74Val	missense	Exon 4 of 6	NP_000321.1
	CDKL5	NM_001037343.2		c.2797+1206C>A		intron	N/A	NP_001032420.1
	CDKL5	NM_003159.3		c.2797+1206C>A		intron	N/A	NP_003150.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.221G>T	p.Gly74Val	missense	Exon 4 of 6	ENSP00000369320.3
	RS1	ENST00000476595.1	TSL:1	n.712G>T		non_coding_transcript_exon	Exon 3 of 5
	CDKL5	ENST00000379989.6	TSL:1	c.2797+1206C>A		intron	N/A	ENSP00000369325.3

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111244 Hom.: 0 Cov.: 22

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: 0.000167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097720 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363148

African (AFR) AF: 0.00 AC: 0 AN: 26386

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: 54129

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3943

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841872

Other (OTH) AF: 0.00 AC: 0 AN: 46061

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111244 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33430

African (AFR) AF: 0.00 AC: 0 AN: 30558

American (AMR) AF: 0.00 AC: 0 AN: 10395

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3556

South Asian (SAS) AF: 0.00 AC: 0 AN: 2649

European-Finnish (FIN) AF: 0.000167 AC: 1 AN: 5986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53062

Other (OTH) AF: 0.00 AC: 0 AN: 1484

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Juvenile retinoschisis (1)
1	-	-	not provided (2)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		5.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.84		Loss of disorder (P = 0.0346)
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.94
Mutation Taster		=22/78	disease causing (ClinVar)

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: rs104894933; hg19: chrX-18665416; COSMIC: COSV107494542;