rs869312848

chr20-492351-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_177559.3(CSNK2A1):c.524A>G(p.Asp175Gly) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D175E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSNK2A1 NM_177559.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.99

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 12 ACMG points.

• PM1: In a domain Protein kinase (size 285) in uniprot entity CSK21_HUMAN there are 36 pathogenic changes around while only 0 benign (100%) 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 chr20-492352-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2504560.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, CSNK2A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 20-492351-T-C is Pathogenic according to our data. Variant chr20-492351-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 224799.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSNK2A1	NM_177559.3	c.524A>G	p.Asp175Gly	missense_variant	9/14	ENST00000217244.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSNK2A1	ENST00000217244.9	c.524A>G	p.Asp175Gly	missense_variant	9/14	1	NM_177559.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Okur-Chung neurodevelopmental syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 05, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;T;T;T;.;T;T;.;.;.;T;.;.;.;.;T;T;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.5	M;M;M;.;.;M;M;.;.;.;M;.;.;.;.;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
Polyphen		0.074	B;B;B;.;.;B;B;.;.;.;B;.;.;.;.;B;B;.;.;.
Vest4		0.98
MutPred		0.96		Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);.;Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);.;.;Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);.;.;.;.;Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);.;
MVP		1.0
MPC		3.4
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.89
gMVP		1.0

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: rs869312848; hg19: chr20-472995;