rs186334493

Variant names:

• chrX-18642103-G-A
• rs186334493
• NM_000330.4:c.576C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-18642103-G-A
• chrX-18642103-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1 BP4 BP7

This summary comes from the ClinGen Evidence Repository: The NM_000330.4(RS1):c.576C>T variant is a synonymous variant at codon 192. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0003976 among hemizygous individuals, with 158 variant alleles / 397377 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.0002 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.00 for all delta-type changes, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). This silent variant causing a synonymous variant at codon 192 does not have an impact at splicing sites according to Splice AI, which predicts a delta score of 0.00 for all delta-type changes which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP7). In summary, this variant is classified as benign for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: BA1, BP4, and BP7 (date of approval 01/24/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10360603/MONDO:0010725/126

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., 13 hem., cov: 23)
  • Exomes 𝑓: 0.00037 (2 hom. 145 hem.)
• Consequence: RS1 NM_000330.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: -1.42
• Publications: 5 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

Specifications for RS1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RS1	NM_000330.4	MANE Select	c.576C>T	p.Pro192Pro	synonymous	Exon 6 of 6	NP_000321.1	O15537
	CDKL5	NM_001037343.2		c.2714-3904G>A		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2714-3904G>A		intron	N/A	NP_003150.1	O76039-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.576C>T	p.Pro192Pro	synonymous	Exon 6 of 6	ENSP00000369320.3	O15537
	CDKL5	ENST00000379989.6	TSL:1	c.2714-3904G>A		intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2714-3904G>A		intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 39 AN: 111804 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000946

Gnomad ASJ AF: 0.00226

Gnomad EAS AF: 0.00706

Gnomad SAS AF: 0.000374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000941

Gnomad OTH AF: 0.000669

GnomAD2 exomes AF: 0.000842 AC: 154 AN: 182969 AF XY: 0.000888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000267

Gnomad EAS exome AF: 0.00909

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000370 AC: 406 AN: 1098005 Hom.: 2 Cov.: 31 AF XY: 0.000399 AC XY: 145 AN XY: 363359

African (AFR) AF: 0.0000379 AC: 1 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.000671 AC: 13 AN: 19385

East Asian (EAS) AF: 0.00761 AC: 230 AN: 30205

South Asian (SAS) AF: 0.00124 AC: 67 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.000485 AC: 2 AN: 4125

European-Non Finnish (NFE) AF: 0.0000796 AC: 67 AN: 841926

Other (OTH) AF: 0.000564 AC: 26 AN: 46087

GnomAD4 genome AF: 0.000349 AC: 39 AN: 111856 Hom.: 0 Cov.: 23 AF XY: 0.000382 AC XY: 13 AN XY: 34018

African (AFR) AF: 0.00 AC: 0 AN: 30792

American (AMR) AF: 0.0000945 AC: 1 AN: 10584

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 6 AN: 2653

East Asian (EAS) AF: 0.00709 AC: 25 AN: 3528

South Asian (SAS) AF: 0.000375 AC: 1 AN: 2664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000941 AC: 5 AN: 53114

Other (OTH) AF: 0.000661 AC: 1 AN: 1514

Alfa AF: 0.000498 Hom.: 3

Bravo AF: 0.000620

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Juvenile retinoschisis (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.5
DANN	Benign	0.89
PhyloP100		-1.4
Mutation Taster		=96/4	polymorphism (auto)

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: rs186334493; hg19: chrX-18660223;