X-18644622-A-T

Position:

• chrX-18644622-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000330.4(RS1):​c.330T>A​(p.Cys110*) variant causes a stop gained 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 (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: RS1 NM_000330.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: -0.532

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]

RS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 31 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-18644622-A-T is Pathogenic according to our data. Variant chrX-18644622-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 98939.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-18644622-A-T is described in Lovd as [Pathogenic]. Variant chrX-18644622-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RS1	NM_000330.4	c.330T>A	p.Cys110*	stop_gained	5/6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.234T>A	p.Cys78*	stop_gained	3/4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-1385A>T		intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2714-1385A>T		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.330T>A	p.Cys110*	stop_gained	5/6	1	NM_000330.4	ENSP00000369320.3
CDKL5	ENST00000379989.6	c.2714-1385A>T		intron_variant		1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2714-1385A>T		intron_variant		1		ENSP00000369332.3
RS1	ENST00000476595.1	n.821T>A		non_coding_transcript_exon_variant	4/5	1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2019	This sequence change creates a premature translational stop signal (p.Cys110*) in the RS1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RS1 are known to be pathogenic (PMID: 9618178, 17172462). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individuals affected with X-linked congenital retinoschisis (PMID: 10636421, 30652005). ClinVar contains an entry for this variant (Variation ID: 98939). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	23
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.22	N
Vest4		0.96
GERP RS		-4.5

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: rs1801161; hg19: chrX-18662742;