X-18642018-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000330.4(RS1):c.661A>G(p.Ser221Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,209,888 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000010 ( 0 hom. 5 hem. )

Consequence

RS1
NM_000330.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.26

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]

RS1 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000330.4

BP4

Computational evidence support a benign effect (MetaRNN=0.10140616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RS1	NM_000330.4 linkuse as main transcript	c.661A>G	p.Ser221Gly	missense_variant	6/6	ENST00000379984.4
RS1	XM_047442337.1 linkuse as main transcript	c.565A>G	p.Ser189Gly	missense_variant	4/4
CDKL5	NM_001037343.2 linkuse as main transcript	c.2714-3989T>C		intron_variant
CDKL5	NM_003159.3 linkuse as main transcript	c.2714-3989T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RS1	ENST00000379984.4 linkuse as main transcript	c.661A>G	p.Ser221Gly	missense_variant	6/6	1	NM_000330.4	P1
CDKL5	ENST00000379989.6 linkuse as main transcript	c.2714-3989T>C		intron_variant		1			O76039-1
CDKL5	ENST00000379996.7 linkuse as main transcript	c.2714-3989T>C		intron_variant		1			O76039-1
RS1	ENST00000476595.1 linkuse as main transcript	n.1152A>G		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112091

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34271

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000282

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:

0.000670

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182869

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67505

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1097797

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363311

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000950

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000446

AC:

AN:

112091

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34271

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.000282

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000670

Bravo

AF:

0.0000982

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 221 of the RS1 protein (p.Ser221Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1404057). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RS1 protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

0.0087

BayesDel_noAF

Benign

-0.23

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.20

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.10

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

0.46

MutationTaster

Benign

1.0

D;D;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.39

Sift

Benign

0.23

Sift4G

Benign

0.18

Polyphen

0.0020

Vest4

0.065

MutPred

0.36

Loss of ubiquitination at K222 (P = 0.1139);

MVP

0.59

MPC

0.58

ClinPred

0.73

GERP RS

4.5

Varity_R

0.31

gMVP

0.88

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over