rs200052722

Variant names:

• chrX-18642082-G-A
• rs200052722
• NM_000330.4:c.597C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-18642082-G-A
• chrX-18642082-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_000330.4(RS1):​c.597C>T​(p.Ile199Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 111,727 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I199I) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 24)
• Consequence: RS1 NM_000330.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36
• Publications: 1 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP7: Synonymous conserved (PhyloP=2.36 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4	c.597C>T	p.Ile199Ile	synonymous_variant	Exon 6 of 6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.501C>T	p.Ile167Ile	synonymous_variant	Exon 4 of 4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-3925G>A		intron_variant	Intron 19 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.2714-3925G>A		intron_variant	Intron 18 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.597C>T	p.Ile199Ile	synonymous_variant	Exon 6 of 6	1	NM_000330.4	ENSP00000369320.3
RS1	ENST00000476595.1	n.1088C>T		non_coding_transcript_exon_variant	Exon 5 of 5	1
CDKL5	ENST00000379989.6	c.2714-3925G>A		intron_variant	Intron 19 of 21	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2714-3925G>A		intron_variant	Intron 18 of 20	1		ENSP00000369332.3

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111727 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111727 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 33877

African (AFR) AF: 0.0000326 AC: 1 AN: 30690

American (AMR) AF: 0.00 AC: 0 AN: 10557

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6089

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53098

Other (OTH) AF: 0.00 AC: 0 AN: 1498

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.1
DANN	Benign	0.91
PhyloP100		2.4
Mutation Taster		=100/0	polymorphism

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: rs200052722; hg19: chrX-18660202;