rs61752060

Positions:

• chrX-18647251-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000330.4(RS1):​c.266A>G​(p.Tyr89Cys) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: RS1 NM_000330.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.67

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 16 ACMG points.

• PM1: In a domain F5/8 type C (size 156) in uniprot entity XLRS1_HUMAN there are 39 pathogenic changes around while only 0 benign (100%) in NM_000330.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-18647251-T-C is Pathogenic according to our data. Variant chrX-18647251-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 98923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18647251-T-C is described in Lovd as [Pathogenic]. Variant chrX-18647251-T-C is described in Lovd as [Pathogenic]. Variant chrX-18647251-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RS1	NM_000330.4	c.266A>G	p.Tyr89Cys	missense_variant	4/6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.170A>G	p.Tyr57Cys	missense_variant	2/4		XP_047298293.1
CDKL5	NM_001037343.2	c.2797+1161T>C		intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2797+1161T>C		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.266A>G	p.Tyr89Cys	missense_variant	4/6	1	NM_000330.4	ENSP00000369320	P1
CDKL5	ENST00000379989.6	c.2797+1161T>C		intron_variant		1		ENSP00000369325
CDKL5	ENST00000379996.7	c.2797+1161T>C		intron_variant		1		ENSP00000369332
RS1	ENST00000476595.1	n.757A>G		non_coding_transcript_exon_variant	3/5	1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile retinoschisis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 02, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 07, 2016	- -

not provided Other:1

not provided, no classification provided

literature only

Retina International

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.73
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.91
Sift	Benign	0.045	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.81		Loss of sheet (P = 0.1158);
MVP		0.99
MPC		1.8
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.76
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs61752060; hg19: chrX-18665371;