dbSNP rs1339570385: RS1:p.Ser221Gly (chrX-18642018-T-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2

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, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.26

Publications

0 publications found

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 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

CDKL5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked retinoschisis, retinoschisis.

BP4

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

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000330.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RS1	NM_000330.4	MANE Select	c.661A>G	p.Ser221Gly	missense	Exon 6 of 6	NP_000321.1	O15537
CDKL5	NM_001037343.2		c.2714-3989T>C		intron	N/A	NP_001032420.1	O76039-1
CDKL5	NM_003159.3		c.2714-3989T>C		intron	N/A	NP_003150.1	O76039-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RS1	ENST00000379984.4	TSL:1 MANE Select	c.661A>G	p.Ser221Gly	missense	Exon 6 of 6	ENSP00000369320.3	O15537
CDKL5	ENST00000379989.6	TSL:1	c.2714-3989T>C		intron	N/A	ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7	TSL:1	c.2714-3989T>C		intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112091

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00000547

AC:

AN:

182869

AF XY:

0.00

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 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

African (AFR)

AF:

0.00

AC:

AN:

26390

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40503

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3830

European-Non Finnish (NFE)

AF:

0.00000950

AC:

AN:

842097

Other (OTH)

AF:

0.0000651

AC:

AN:

46052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000446

AC:

AN:

112091

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34271

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30820

American (AMR)

AF:

0.000282

AC:

AN:

10642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3547

South Asian (SAS)

AF:

0.00

AC:

AN:

2681

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6157

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53185

Other (OTH)

AF:

0.000670

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000982

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

0.0087

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

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

PhyloP100

3.3

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

Mutation Taster

=68/32

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over