chrX-18642103-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1BP4BP7

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

Scores

Clinical Significance

Benign reviewed by expert panel B:3

Conservation

PhyloP100: -1.42

Publications

5 publications found

Variant links:

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]

RS1 links:

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

CDKL5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4 link	c.576C>T	p.Pro192Pro	synonymous_variant	Exon 6 of 6	ENST00000379984.4	NP_000321.1	O15537
RS1	XM_047442337.1 link	c.480C>T	p.Pro160Pro	synonymous_variant	Exon 4 of 4		XP_047298293.1
CDKL5	NM_001037343.2 link	c.2714-3904G>A		intron_variant	Intron 19 of 21		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.2714-3904G>A		intron_variant	Intron 18 of 20		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RS1	ENST00000379984.4 link	c.576C>T	p.Pro192Pro	synonymous_variant	Exon 6 of 6	1	NM_000330.4	ENSP00000369320.3	O15537
RS1	ENST00000476595.1 link	n.1067C>T		non_coding_transcript_exon_variant	Exon 5 of 5	1
CDKL5	ENST00000379989.6 link	c.2714-3904G>A		intron_variant	Intron 19 of 21	1		ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7 link	c.2714-3904G>A		intron_variant	Intron 18 of 20	1		ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes

AF:

0.000349

AC:

AN:

111804

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.000399

AC XY:

145

AN XY:

363359

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.000671

AC:

AN:

19385

East Asian (EAS)

AF:

0.00761

AC:

230

AN:

30205

South Asian (SAS)

AF:

0.00124

AC:

AN:

54142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.000485

AC:

AN:

4125

European-Non Finnish (NFE)

AF:

0.0000796

AC:

AN:

841926

Other (OTH)

AF:

0.000564

AC:

AN:

46087

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000349

AC:

AN:

111856

Hom.:

Cov.:

AF XY:

0.000382

AC XY:

AN XY:

34018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30792

American (AMR)

AF:

0.0000945

AC:

AN:

10584

Ashkenazi Jewish (ASJ)

AF:

0.00226

AC:

AN:

2653

East Asian (EAS)

AF:

0.00709

AC:

AN:

3528

South Asian (SAS)

AF:

0.000375

AC:

AN:

2664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000941

AC:

AN:

53114

Other (OTH)

AF:

0.000661

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000498

Hom.:

Bravo

AF:

0.000620

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely 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.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). -

not provided

Benign:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

6.5

(source)

DANN

Benign

0.89

PhyloP100

-1.4

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chrX-18642103-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over