rs1555764992

Positions:

• chr20-505178-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_177559.3(CSNK2A1):​c.153T>A​(p.Ser51Arg) variant causes a missense change involving the alteration of a non-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: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.48

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 Likely_pathogenic. Variant got 9 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, 0.927
• PP5: Variant 20-505178-A-T is Pathogenic according to our data. Variant chr20-505178-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559896.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSNK2A1	NM_177559.3	c.153T>A	p.Ser51Arg	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.153T>A	p.Ser51Arg	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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Okur-Chung neurodevelopmental syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Nov 03, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T;T;T;T;.;.;.;T;.;.;.;T;T;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	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	0.072	D
MetaRNN	Pathogenic	0.93	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	-0.88	T
MutationAssessor	Pathogenic	3.7	H;H;H;.;H;H;.;.;.;H;.;.;.;H;H;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.7	.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.82	P;P;P;.;P;P;.;.;.;P;.;.;.;P;P;.;.;.;.;.;.;.;.;.
Vest4		0.95, 0.95
MutPred		0.85		Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);Gain of MoRF binding (P = 0.0059);
MVP		0.93
MPC		3.1
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.98

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: rs1555764992; hg19: chr20-485822;