chrX-18642015-T-TG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_000330.4(RS1):​c.663_664insC​(p.Lys222GlnfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,694 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

RS1
NM_000330.4 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.21
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RS1NM_000330.4 linkuse as main transcriptc.663_664insC p.Lys222GlnfsTer42 frameshift_variant 6/6 ENST00000379984.4
RS1XM_047442337.1 linkuse as main transcriptc.567_568insC p.Lys190GlnfsTer42 frameshift_variant 4/4
CDKL5NM_001037343.2 linkuse as main transcriptc.2714-3991dup intron_variant
CDKL5NM_003159.3 linkuse as main transcriptc.2714-3991dup intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RS1ENST00000379984.4 linkuse as main transcriptc.663_664insC p.Lys222GlnfsTer42 frameshift_variant 6/61 NM_000330.4 P1
CDKL5ENST00000379989.6 linkuse as main transcriptc.2714-3991dup intron_variant 1 O76039-1
CDKL5ENST00000379996.7 linkuse as main transcriptc.2714-3991dup intron_variant 1 O76039-1
RS1ENST00000476595.1 linkuse as main transcriptn.1154_1155insC non_coding_transcript_exon_variant 5/51

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
9.11e-7
AC:
1
AN:
1097694
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
363246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, no assertion criteria providedliterature onlySN ONGC Dept of Genetics and Molecular biology Vision Research Foundation-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199469700; hg19: chrX-18660135; API