chrX-18642002-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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 (no stars).

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

Scores

2

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.187
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 Benign. Variant got -13 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 no_assertion_criteria_provided, 0 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 GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RS1NM_000330.4 linkc.*2G>T 3_prime_UTR_variant Exon 6 of 6 ENST00000379984.4 NP_000321.1 O15537
RS1XM_047442337.1 linkc.*2G>T 3_prime_UTR_variant Exon 4 of 4 XP_047298293.1
CDKL5NM_001037343.2 linkc.2714-4005C>A intron_variant Intron 19 of 21 NP_001032420.1 O76039-1
CDKL5NM_003159.3 linkc.2714-4005C>A intron_variant Intron 18 of 20 NP_003150.1 O76039-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RS1ENST00000379984 linkc.*2G>T 3_prime_UTR_variant Exon 6 of 6 1 NM_000330.4 ENSP00000369320.3 O15537
CDKL5ENST00000379989.6 linkc.2714-4005C>A intron_variant Intron 19 of 21 1 ENSP00000369325.3 O76039-1
CDKL5ENST00000379996.7 linkc.2714-4005C>A intron_variant Intron 18 of 20 1 ENSP00000369332.3 O76039-1
RS1ENST00000476595.1 linkn.1168G>T non_coding_transcript_exon_variant Exon 5 of 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
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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: no assertion criteria provided
LINK: link

Submissions by phenotype

RS1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 28, 2019This 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

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

Other links and lift over

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