chr20-505191-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong

The NM_177559.3(CSNK2A1):c.140G>A(p.Arg47Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R47P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CSNK2A1
NM_177559.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.89

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

Okur-Chung neurodevelopmental syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, G2P
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

CSNK2A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_177559.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-505191-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4235181.Status of the report is criteria_provided_single_submitter, 1 stars.

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 Okur-Chung neurodevelopmental syndrome, syndromic intellectual disability.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.796

PP5

Variant 20-505191-C-T is Pathogenic according to our data. Variant chr20-505191-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSNK2A1	NM_177559.3 link	c.140G>A	p.Arg47Gln	missense_variant	Exon 4 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.140G>A	p.Arg47Gln	missense_variant	Exon 4 of 14	1	NM_177559.3	ENSP00000217244.3		P68400-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000426

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Okur-Chung neurodevelopmental syndrome

Pathogenic:8

Sep 20, 2024

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). The mechanism of missense variants is unclear. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as likely pathogenic and pathogenic (ClinVar), and observed as de novo in multiple individuals with developmental delay (VCGS, DECIPHER, PMID: 27048600; PMID: 29383814). (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 -

Jun 26, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 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 2019-01-16 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. -

Oct 02, 2021

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least two similarly affected unrelated individuals (ClinVar ID: VCV000224796.3, PMID:28135719, 29240241, 27048600, and 29383814, PS2 and PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg47Gly) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280816.3, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

This variant in the CSNK2A1 gene is classified as Pathogenic based on multiple lines of evidence. It is located in the Protein kinase domain and a known hot-spot region, both enriched with pathogenic variants, fulfilling PM1 (Strong). ClinVar classifies the variant as Pathogenic (2 stars), supported by high-confidence submissions and multiple publications, meeting PP5 (Strong). Additionally, an alternative variant (Arg47Gly) at the same residue is classified as Pathogenic, supporting PM5 (Moderate). The variant is absent in gnomAD genomes and exomes, fulfilling PM2 (Supporting), and in silico tools (MetaRNN = 0.796) predict a deleterious effect, fulfilling PP3 (Supporting). Together, these findings confirm the variant as Pathogenic per ACMG/AMP guidelines. -

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 13, 2022

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 05, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Pathogenic:1

May 03, 2017

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

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

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Benign

0.053

MetaRNN

Pathogenic

0.80

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

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.53

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

PhyloP100

7.9

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.6

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

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.053

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

Polyphen

1.0

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

Vest4

0.79, 0.79

MutPred

0.58

Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);

MVP

0.85

MPC

2.9

ClinPred

1.0

GERP RS

4.6

Varity_R

0.95

gMVP

0.64

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over