chr20-492282-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP2PP5_Very_Strong

The NM_177559.3(CSNK2A1):c.593A>G(p.Lys198Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CSNK2A1
NM_177559.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22

Conservation

PhyloP100: 7.99

Variant links:

Genes affected

CSNK2A1 (HGNC:2457): (casein kinase 2 alpha 1) Casein kinase II is a serine/threonine protein kinase that phosphorylates acidic proteins such as casein. It is involved in various cellular processes, including cell cycle control, apoptosis, and circadian rhythm. The kinase exists as a tetramer and is composed of an alpha, an alpha-prime, and two beta subunits. The alpha subunits contain the catalytic activity while the beta subunits undergo autophosphorylation. The protein encoded by this gene represents the alpha subunit. Multiple transcript variants encoding different protein isoforms have been found for this gene. [provided by RefSeq, Apr 2018]

CSNK2A1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the CSNK2A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 28 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 3.7123 (above the threshold of 3.09). Trascript score misZ: 5.3205 (above the threshold of 3.09). GenCC associations: The gene is linked to syndromic intellectual disability, Okur-Chung neurodevelopmental syndrome.

PP5

Variant 20-492282-T-C is Pathogenic according to our data. Variant chr20-492282-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-492282-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSNK2A1	NM_177559.3 link	c.593A>G	p.Lys198Arg	missense_variant	Exon 9 of 14	ENST00000217244.9	NP_808227.1	P68400-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSNK2A1	ENST00000217244.9 link	c.593A>G	p.Lys198Arg	missense_variant	Exon 9 of 14	1	NM_177559.3	ENSP00000217244.3		P68400-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251364

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135852

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727220

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Okur-Chung neurodevelopmental syndrome

Pathogenic:14

Jun 23, 2023

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The heterozygous de-novo variant c.593A>G (p.Lys198Arg) has been identified in a 4months old female proband with seizures, bilateral cherry red spots, multiple episodes of apnea and cyanosis, generalized edema, dyskinetic movements of both upper limbs. This variant is identified in exon 8 which is a hotspot exon for CSNK2A1 gene (PM1_supporting). 26 pathogenic mis-sense variants have been identified in this gene (PP2_supporting). The population frequency in gnomAD (aggregated) is 0.0004% (PM2_moderate). This variant has been identified previously PMID 27048600 (PP5_very strong). -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Okur-Chung neurodevelopmental syndrome (MIM#617062). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least ten individuals with Okur-Chung neurodevelopmental syndrome (MIM#617062), the majority of whom were due to de novo events (ClinVar, PMID: 29383814, 30655572). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 27048600, 29619237, 29383814, 29240241, PS2_VS). It has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 27048600, 29619237, 29383814, 29240241). A missense variant is a common mechanism . It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 07, 2022

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP2+PS4_Moderate+PM6_Strong+PM1 -

Mar 13, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS3-SUP, PS4, PM2_SUP, PP2 -

Dec 11, 2023

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.593A>G (p.Lys198Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a de novo change in individuals with Okur-Chung neurodevelopmental syndrome (OCNDS) (PMID: 27048600, 29619237, 30655572, 29383814). The c.593A>G (p.Lys198Arg) variant is located in a mutational hotspot for pathogenic variations associated with OCNDS (PMID: 35679446). Functional studies indicate this variant may lead to an alteration of substrate specificity (PMID: 35445078). The c.593A>G (p.Lys198Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/251364) and thus is presumed to be rare. Based on the available evidence, c.593A>G (p.Lys198Arg) is classified as Pathogenic. -

Nov 27, 2020

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Lys198Arg variant in the CSNK2A1 gene has been previously reported de novo in 8 unrelated individuals with Okur-Chung neurodevelopmental syndrome (Okur et al., 2016; Owen et al., 2017; Chiu et al., 2018; Akahira-Azuma et al., 2018; Nakashima et al., 2019). This variant has also been identified in 1/251361 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The CSNK2A1 gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Lys198Arg variant as pathogenic for autosomal dominant Okur-Chung neurodevelopmental syndrome based on the information above. [ACMG evidence codes used: PS2; PS4; PP2] -

Jul 22, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Apr 27, 2020

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 08, 2019

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-02-08 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. -

Nov 02, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 20, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 04, 2022

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4;PM1;PM2_supporting;PM6;PP2;PP3 -

not provided

Pathogenic:5

Aug 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed to be de novo in individuals affected with Okur-Chung neurodevelopmental syndrome (PMID: 27048600, 29619237, 29383814, 29240241). ClinVar contains an entry for this variant (Variation ID: 224790). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 198 of the CSNK2A1 protein (p.Lys198Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. -

Jun 09, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (altered binding specificity) (Caefer et al., 2022; Werner et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30655572, 32746809, 27048600, 29619237, 25363768, 28135719, 29383814, 28191890, 30109123, 29240241, 31060130, 28714951, 32651551, 34011629, 33726816, 31785789, 33994545, 35445078, 33944995, 35517865) -

Apr 26, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodevelopmental delay

Pathogenic:1

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Mar 07, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.593A>G (p.K198R) alteration is located in exon 9 (coding exon 7) of the CSNK2A1 gene. This alteration results from an A to G substitution at nucleotide position 593, causing the lysine (K) at amino acid position 198 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of <0.01% (1/251364) total alleles studied. The p.K198R alteration is the most common alteration in Okur-Chung syndrome and has been reported as de novo in multiple patients (Iossifov, 2014; Okur, 2016; Akahira-Azuma, 2018; Owen, 2018; Chiu, 2018). Based on the available evidence, this alteration is classified as pathogenic. -

See cases

Pathogenic:1

Apr 26, 2021

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_strong;PM2_supporting;PM6_moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T;T;T;.;T;T;.;.;.;T;.;.;.;.;T;T;.;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

.;.;.;D;.;.;.;D;.;D;.;D;.;D;D;.;D;D;D

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.66

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.095

N;N;N;.;.;N;N;.;.;.;N;.;.;.;.;N;N;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.9

.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.062

.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.89

P;P;P;.;.;P;P;.;.;.;P;.;.;.;.;P;P;.;.

Vest4

0.87, 0.88

MutPred

0.70

Loss of ubiquitination at K198 (P = 0.0309);Loss of ubiquitination at K198 (P = 0.0309);Loss of ubiquitination at K198 (P = 0.0309);Loss of ubiquitination at K198 (P = 0.0309);.;Loss of ubiquitination at K198 (P = 0.0309);Loss of ubiquitination at K198 (P = 0.0309);.;.;Loss of ubiquitination at K198 (P = 0.0309);Loss of ubiquitination at K198 (P = 0.0309);.;.;.;.;Loss of ubiquitination at K198 (P = 0.0309);Loss of ubiquitination at K198 (P = 0.0309);Loss of ubiquitination at K198 (P = 0.0309);Loss of ubiquitination at K198 (P = 0.0309);

MVP

0.90

MPC

2.3

ClinPred

0.95

GERP RS

4.8

Varity_R

0.92

gMVP

0.91

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