chrX-18642103-G-A

Position:

• chrX-18642103-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000330.4(RS1):​c.576C>T​(p.Pro192Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,209,861 control chromosomes in the GnomAD database, including 2 homozygotes. There are 158 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 0.00035 (0 hom., 13 hem., cov: 23)
  • Exomes 𝑓: 0.00037 (2 hom. 145 hem.)
• Consequence: RS1 NM_000330.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.42

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=-0.56).
• BP6: Variant X-18642103-G-A is Benign according to our data. Variant chrX-18642103-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18642103-G-A is described in Lovd as [Benign]. Variant chrX-18642103-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000349 (39/111856) while in subpopulation EAS AF= 0.00709 (25/3528). AF 95% confidence interval is 0.00493. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RS1	NM_000330.4	c.576C>T	p.Pro192Pro	synonymous_variant	6/6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.480C>T	p.Pro160Pro	synonymous_variant	4/4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-3904G>A		intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2714-3904G>A		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.576C>T	p.Pro192Pro	synonymous_variant	6/6	1	NM_000330.4	ENSP00000369320.3
CDKL5	ENST00000379989.6	c.2714-3904G>A		intron_variant		1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2714-3904G>A		intron_variant		1		ENSP00000369332.3
RS1	ENST00000476595.1	n.1067C>T		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 39 AN: 111804 Hom.: 0 Cov.: 23 AF XY: 0.000383 AC XY: 13 AN XY: 33956

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

GnomAD3 exomes AF: 0.000842 AC: 154 AN: 182969 Hom.: 1 AF XY: 0.000888 AC XY: 60 AN XY: 67591

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 SAS exome AF: 0.00115

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

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000671

Gnomad4 EAS exome AF: 0.00761

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000796

Gnomad4 OTH exome AF: 0.000564

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000945

Gnomad4 ASJ AF: 0.00226

Gnomad4 EAS AF: 0.00709

Gnomad4 SAS AF: 0.000375

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000941

Gnomad4 OTH AF: 0.000661

Alfa AF: 0.000498 Hom.: 3

Bravo AF: 0.000620

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.5
DANN	Benign	0.89

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: rs186334493; hg19: chrX-18660223;