20-505182-T-C

Position:

• chr20-505182-T-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000217244.9(CSNK2A1):​c.149A>G​(p.Tyr50Cys) 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. Y50S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CSNK2A1 ENST00000217244.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.00

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 19 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, 1 uncertain in ENST00000217244.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-505182-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 224800.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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, 0.946
• PP5: Variant 20-505182-T-C is Pathogenic according to our data. Variant chr20-505182-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-505182-T-C is described in Lovd as [Pathogenic]. Variant chr20-505182-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSNK2A1	NM_177559.3	c.149A>G	p.Tyr50Cys	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.149A>G	p.Tyr50Cys	missense_variant	4/14	1	NM_177559.3	ENSP00000217244	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Jan 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2022	Not observed at significant frequency in large population cohorts (gnomAD); 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: 31729156, 34038195, 33994545, 32472542, 32371413) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Okur-Chung neurodevelopmental syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Mar 26, 2018	[ACMG/AMP: PS2, PM2, PM5, PP2, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jul 31, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 24, 2022	ACMG classification criteria: PS4 supporting, PM2 moderate, PM5, PP2 supporting, PP3 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T;T;T;T;.;.;.;T;.;.;.;T;T;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;.;.;D;.;.;D;.;D;.;D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.95	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	-0.83	T
MutationAssessor	Uncertain	2.5	M;M;M;.;M;M;.;.;.;M;.;.;.;M;M;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-8.4	.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;D;.;D;D;.;.;.;D;.;.;.;D;D;.;.;.;.;.;.;.;.;.
Vest4		0.92, 0.93
MutPred		0.85		Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);Gain of methylation at K49 (P = 0.0204);
MVP		0.91
MPC		3.3
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.98
gMVP		0.90

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: rs869312849; hg19: chr20-485826;