rs869312845

Positions:

• chr20-505191-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSNK2A1 NM_177559.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.89

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a domain Protein kinase (size 285) in uniprot entity CSK21_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_177559.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CSNK2A1. . Gene score misZ 3.7123 (greater than the threshold 3.09). Trascript score misZ 5.3205 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, Okur-Chung neurodevelopmental syndrome.
• 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 [Likely_pathogenic]. Clinvar id is 224796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSNK2A1	NM_177559.3	c.140G>A	p.Arg47Gln	missense_variant	4/14	ENST00000217244.9	NP_808227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSNK2A1	ENST00000217244.9	c.140G>A	p.Arg47Gln	missense_variant	4/14	1	NM_177559.3	ENSP00000217244	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Okur-Chung neurodevelopmental syndrome Pathogenic:6

Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Jan 16, 2019	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jun 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	34
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	D
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	D
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	T
MutationAssessor	Benign	0.53	N;N;N;.;N;N;.;.;.;N;.;.;.;N;N;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
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	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs869312845; hg19: chr20-485835; COSMIC: COSV53935145; COSMIC: COSV53935145;