rs104894932

Positions:

• chrX-18647301-C-G
• chrX-18647301-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000330.4(RS1):​c.216G>C​(p.Glu72Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E72K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: RS1 NM_000330.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.16

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000330.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-18647303-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-18647301-C-G is Pathogenic according to our data. Variant chrX-18647301-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 9889.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-18647301-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RS1	NM_000330.4	c.216G>C	p.Glu72Asp	missense_variant	4/6	ENST00000379984.4
RS1	XM_047442337.1	c.120G>C	p.Glu40Asp	missense_variant	2/4
CDKL5	NM_001037343.2	c.2797+1211C>G		intron_variant
CDKL5	NM_003159.3	c.2797+1211C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RS1	ENST00000379984.4	c.216G>C	p.Glu72Asp	missense_variant	4/6	1	NM_000330.4	P1
CDKL5	ENST00000379989.6	c.2797+1211C>G		intron_variant		1
CDKL5	ENST00000379996.7	c.2797+1211C>G		intron_variant		1
RS1	ENST00000476595.1	n.707G>C		non_coding_transcript_exon_variant	3/5	1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Juvenile retinoschisis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1998

- -

not provided Other:1

not provided, no classification provided

literature only

Retina International

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.94		Loss of methylation at K67 (P = 0.1122);
MVP		0.99
MPC		1.6
ClinPred		0.98	D
GERP RS		2.3
Varity_R		0.85
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894932; hg19: chrX-18665421;