rs869312849

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 8.00

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 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/exons	MANE	Protein	UniProt
CSNK2A1	NM_177559.3 link	c.149A>G	p.Tyr50Cys	missense_variant	4/14	ENST00000217244.9	NP_808227.1	P68400-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSNK2A1	ENST00000217244.9 link	c.149A>G	p.Tyr50Cys	missense_variant	4/14	1	NM_177559.3	ENSP00000217244.3		P68400-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Okur-Chung neurodevelopmental syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jul 31, 2023	- -
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]. -
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

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

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

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

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

MutationAssessor

Uncertain

2.5

M;M;M;.;M;M;.;.;.;M;.;.;.;M;M;.;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.95

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

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

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