rs869312849

Variant names:

• chr20-505182-T-C
• rs869312849
• ENST00000349736.10:c.-260A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-505182-T-C
• chr20-505182-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_177560.3(CSNK2A1):​c.-260A>G variant causes a 5 prime UTR premature start codon gain 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: 33)
• Consequence: CSNK2A1 NM_177560.3 5_prime_UTR_premature_start_codon_gain
• 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
CSNK2A1	NM_177559.3	c.149A>G	p.Tyr50Cys	missense_variant	Exon 4 of 14	ENST00000217244.9	NP_808227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSNK2A1	ENST00000217244.9	c.149A>G	p.Tyr50Cys	missense_variant	Exon 4 of 14	1	NM_177559.3	ENSP00000217244.3

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

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 02, 2018

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Okur-Chung neurodevelopmental syndrome Pathogenic:3

Mar 26, 2018

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

[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]. -

Jul 31, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.;.;.;.;.;.;.;.
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;