rs1801161

Positions:

• chrX-18644622-A-G
• chrX-18644622-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000330.4(RS1):​c.330T>C​(p.Cys110Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,207,705 control chromosomes in the GnomAD database, including 1,103 homozygotes. There are 5,657 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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 criteria provided, multiple submitters, no conflicts B:4 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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant X-18644622-A-G is Benign according to our data. Variant chrX-18644622-A-G is described in ClinVar as [Benign]. Clinvar id is 98940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18644622-A-G is described in Lovd as [Benign]. Variant chrX-18644622-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.532 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RS1	NM_000330.4	c.330T>C	p.Cys110Cys	synonymous_variant	5/6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.234T>C	p.Cys78Cys	synonymous_variant	3/4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-1385A>G		intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2714-1385A>G		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.330T>C	p.Cys110Cys	synonymous_variant	5/6	1	NM_000330.4	ENSP00000369320.3
CDKL5	ENST00000379989.6	c.2714-1385A>G		intron_variant		1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2714-1385A>G		intron_variant		1		ENSP00000369332.3
RS1	ENST00000476595.1	n.821T>C		non_coding_transcript_exon_variant	4/5	1

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 7060 AN: 110523 Hom.: 519 Cov.: 22 AF XY: 0.0559 AC XY: 1833 AN XY: 32801

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

GnomAD3 exomes AF: 0.0240 AC: 4390 AN: 182980 Hom.: 268 AF XY: 0.0176 AC XY: 1190 AN XY: 67490

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 SAS exome AF: 0.00283

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

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.0189

Gnomad4 ASJ exome AF: 0.0372

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00277

Gnomad4 FIN exome AF: 0.00380

Gnomad4 NFE exome AF: 0.00502

Gnomad4 OTH exome AF: 0.0236

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

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.0278

Gnomad4 ASJ AF: 0.0398

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00403

Gnomad4 FIN AF: 0.00382

Gnomad4 NFE AF: 0.00523

Gnomad4 OTH AF: 0.0587

Alfa AF: 0.0359 Hom.: 263

Bravo AF: 0.0748

EpiCase AF: 0.00845

EpiControl AF: 0.00664

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.079
DANN	Benign	0.56

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: rs1801161; hg19: chrX-18662742;