X-18642002-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000330.4(RS1):c.*2G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000332 in 1,209,631 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 119 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 10 hem., cov: 23)
  • Exomes 𝑓: 0.00034 (0 hom. 109 hem.)
• Consequence: RS1 NM_000330.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.187

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-18642002-C-A is Benign according to our data. Variant chrX-18642002-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3035108.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000344 (377/1097418) while in subpopulation NFE AF= 0.00041 (345/842052). AF 95% confidence interval is 0.000374. There are 0 homozygotes in gnomad4_exome. There are 109 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RS1	NM_000330.4	c.*2G>T		3_prime_UTR_variant	6/6	ENST00000379984.4
RS1	XM_047442337.1	c.*2G>T		3_prime_UTR_variant	4/4
CDKL5	NM_001037343.2	c.2714-4005C>A		intron_variant
CDKL5	NM_003159.3	c.2714-4005C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RS1	ENST00000379984.4	c.*2G>T		3_prime_UTR_variant	6/6	1	NM_000330.4	P1
CDKL5	ENST00000379989.6	c.2714-4005C>A		intron_variant		1
CDKL5	ENST00000379996.7	c.2714-4005C>A		intron_variant		1
RS1	ENST00000476595.1	n.1168G>T		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.000214 AC: 24 AN: 112213 Hom.: 0 Cov.: 23 AF XY: 0.000291 AC XY: 10 AN XY: 34383

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000376

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000666

GnomAD3 exomes AF: 0.000181 AC: 33 AN: 182349 Hom.: 0 AF XY: 0.000134 AC XY: 9 AN XY: 67199

Gnomad AFR exome AF: 0.0000768

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000344 AC: 377 AN: 1097418 Hom.: 0 Cov.: 31 AF XY: 0.000300 AC XY: 109 AN XY: 363138

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000410

Gnomad4 OTH exome AF: 0.000413

GnomAD4 genome AF: 0.000214 AC: 24 AN: 112213 Hom.: 0 Cov.: 23 AF XY: 0.000291 AC XY: 10 AN XY: 34383

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.000376

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.000666

Alfa AF: 0.000498 Hom.: 3

Bravo AF: 0.000219

EpiCase AF: 0.000654

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

RS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.57
Dann	Benign	0.86

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: rs756606916; hg19: chrX-18660122; COSMIC: COSV66107429; COSMIC: COSV66107429;