rs1801161

Variant names:

• chrX-18644622-A-G
• rs1801161
• NM_000330.4:c.330T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-18644622-A-G
• chrX-18644622-A-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.330T>C variant is a synonymous variant at amino acid 110. This variant is present in gnomAD v.4.1.0 at a frequency of 0.01431 among hemizygous individuals, with 5657 variant alleles / 395399 total hemizygous 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 predictive splice 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 c.330T>C causing a synonymous variant at codon 110 does not have an impact at splicing sites according to Splice AI, which predicts a delta score of 0.00 for all predictive splice 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/CA226691/MONDO:0010725/126

• Frequency:
  • Genomes: 𝑓 0.064 (518 hom., 1856 hem., cov: 22)
  • Exomes 𝑓: 0.012 (585 hom. 3801 hem.)
• Consequence: RS1 NM_000330.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:5 O:1
• Conservation: PhyloP100: -0.532
• Publications: 4 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: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RS1	NM_000330.4	MANE Select	c.330T>C	p.Cys110Cys	synonymous	Exon 5 of 6	NP_000321.1
	CDKL5	NM_001037343.2		c.2714-1385A>G		intron	N/A	NP_001032420.1
	CDKL5	NM_003159.3		c.2714-1385A>G		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.330T>C	p.Cys110Cys	synonymous	Exon 5 of 6	ENSP00000369320.3
	RS1	ENST00000476595.1	TSL:1	n.821T>C		non_coding_transcript_exon	Exon 4 of 5
	CDKL5	ENST00000379989.6	TSL:1	c.2714-1385A>G		intron	N/A	ENSP00000369325.3

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 7060 AN: 110523 Hom.: 519 Cov.: 22

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00401

Gnomad FIN AF: 0.00382

Gnomad MID AF: 0.0588

Gnomad NFE AF: 0.00527

Gnomad OTH AF: 0.0595

GnomAD2 exomes AF: 0.0240 AC: 4390 AN: 182980 AF XY: 0.0176

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.0367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00306

Gnomad NFE exome AF: 0.00591

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0119 AC: 13045 AN: 1097127 Hom.: 585 Cov.: 31 AF XY: 0.0105 AC XY: 3801 AN XY: 362533

African (AFR) AF: 0.226 AC: 5969 AN: 26371

American (AMR) AF: 0.0189 AC: 667 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 720 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00277 AC: 150 AN: 54112

European-Finnish (FIN) AF: 0.00380 AC: 154 AN: 40528

Middle Eastern (MID) AF: 0.0194 AC: 77 AN: 3975

European-Non Finnish (NFE) AF: 0.00502 AC: 4222 AN: 841323

Other (OTH) AF: 0.0236 AC: 1086 AN: 46039

GnomAD4 genome AF: 0.0641 AC: 7089 AN: 110578 Hom.: 518 Cov.: 22 AF XY: 0.0565 AC XY: 1856 AN XY: 32866

African (AFR) AF: 0.208 AC: 6281 AN: 30218

American (AMR) AF: 0.0278 AC: 293 AN: 10546

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 104 AN: 2616

East Asian (EAS) AF: 0.00 AC: 0 AN: 3493

South Asian (SAS) AF: 0.00403 AC: 10 AN: 2483

European-Finnish (FIN) AF: 0.00382 AC: 23 AN: 6027

Middle Eastern (MID) AF: 0.0599 AC: 13 AN: 217

European-Non Finnish (NFE) AF: 0.00523 AC: 276 AN: 52781

Other (OTH) AF: 0.0587 AC: 89 AN: 1516

Alfa AF: 0.0501 Hom.: 724

Bravo AF: 0.0748

EpiCase AF: 0.00845

EpiControl AF: 0.00664

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3 Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Juvenile retinoschisis Benign:1

May 19, 2025

ClinGen X-linked Inherited Retinal Disease Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000330.4(RS1):c.330T>C variant is a synonymous variant at amino acid 110. This variant is present in gnomAD v.4.1.0 at a frequency of 0.01431 among hemizygous individuals, with 5657 variant alleles / 395399 total hemizygous 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 predictive splice 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 c.330T>C causing a synonymous variant at codon 110 does not have an impact at splicing sites according to Splice AI, which predicts a delta score of 0.00 for all predictive splice 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).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.079
DANN	Benign	0.56
PhyloP100		-0.53
Mutation Taster		=98/2	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: rs1801161; hg19: chrX-18662742;