X-18642018-T-C

Variant names:

• chrX-18642018-T-C
• rs1339570385
• NM_000330.4:c.661A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.26

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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 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
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 0.96911 (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked retinoschisis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10140616).
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4	c.661A>G	p.Ser221Gly	missense_variant	Exon 6 of 6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.565A>G	p.Ser189Gly	missense_variant	Exon 4 of 4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-3989T>C		intron_variant	Intron 19 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.2714-3989T>C		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.661A>G	p.Ser221Gly	missense_variant	Exon 6 of 6	1	NM_000330.4	ENSP00000369320.3
CDKL5	ENST00000379989.6	c.2714-3989T>C		intron_variant	Intron 19 of 21	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2714-3989T>C		intron_variant	Intron 18 of 20	1		ENSP00000369332.3
RS1	ENST00000476595.1	n.1152A>G		non_coding_transcript_exon_variant	Exon 5 of 5	1

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112091 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182869 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1097797 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363311

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 26390

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 35207

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19384

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 30206

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 54128

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40503

Gnomad4 NFE exome AF: 0.00000950 AC: 8 AN: 842097

Gnomad4 Remaining exome AF: 0.0000651 AC: 3 AN: 46052

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 112091 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34271

Gnomad4 AFR AF: 0.0000324 AC: 0.0000324465 AN: 0.0000324465

Gnomad4 AMR AF: 0.000282 AC: 0.000281902 AN: 0.000281902

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.000670 AC: 0.000670241 AN: 0.000670241

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000982

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.661A>G (p.S221G) alteration is located in exon 6 (coding exon 6) of the RS1 gene. This alteration results from a A to G substitution at nucleotide position 661, causing the serine (S) at amino acid position 221 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Jan 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.46	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.39
Sift	Benign	0.23	T
Sift4G	Benign	0.18	T
Polyphen		0.0020	B
Vest4		0.065
MutPred		0.36		Loss of ubiquitination at K222 (P = 0.1139);
MVP		0.59
MPC		0.58
ClinPred		0.73	D
GERP RS		4.5
Varity_R		0.31
gMVP		0.88
Mutation Taster		=68/32	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

Publications

LitVar

Other links and lift over

dbSNP: rs1339570385; hg19: chrX-18660138;