rs1555762734

Variant names:

• chr20-492346-C-T
• rs1555762734
• NM_177559.3:c.529G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_177559.3(CSNK2A1):​c.529G>A​(p.Gly177Ser) 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. G177D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSNK2A1 NM_177559.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.88
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Okur-Chung neurodevelopmental syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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, 3 uncertain 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 chr20-492345-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1685288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the CSNK2A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 28 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 3.7123 (above the threshold of 3.09). Trascript score misZ: 5.3205 (above the threshold of 3.09). GenCC associations: The gene is linked to Okur-Chung neurodevelopmental syndrome, syndromic intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 20-492346-C-T is Pathogenic according to our data. Variant chr20-492346-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 522077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSNK2A1	NM_177559.3	c.529G>A	p.Gly177Ser	missense_variant	Exon 9 of 14	ENST00000217244.9	NP_808227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSNK2A1	ENST00000217244.9	c.529G>A	p.Gly177Ser	missense_variant	Exon 9 of 14	1	NM_177559.3	ENSP00000217244.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Okur-Chung neurodevelopmental syndrome Pathogenic:2

Sep 14, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PM1, PM2, PP2, PP3 -

Feb 16, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Sep 19, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;T;T;.;T;T;.;.;.;T;.;.;.;.;T;T;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;.;D;.;.;.;D;.;D;.;D;.;D;D;.;D;D;D;D
M_CAP	Uncertain	0.23	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	0.98	D
MutationAssessor	Uncertain	2.7	M;M;M;.;.;M;M;.;.;.;M;.;.;.;.;M;M;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.9	.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.014	.;.;.;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;D;.;.;D;D;.;.;.;D;.;.;.;.;D;D;.;.;.
Vest4		0.89, 0.89
MutPred		0.97		Loss of catalytic residue at D175 (P = 0.1676);Loss of catalytic residue at D175 (P = 0.1676);Loss of catalytic residue at D175 (P = 0.1676);Loss of catalytic residue at D175 (P = 0.1676);.;Loss of catalytic residue at D175 (P = 0.1676);Loss of catalytic residue at D175 (P = 0.1676);.;.;Loss of catalytic residue at D175 (P = 0.1676);Loss of catalytic residue at D175 (P = 0.1676);.;.;.;.;Loss of catalytic residue at D175 (P = 0.1676);Loss of catalytic residue at D175 (P = 0.1676);Loss of catalytic residue at D175 (P = 0.1676);Loss of catalytic residue at D175 (P = 0.1676);.;
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555762734; hg19: chr20-472990; COSMIC: COSV53937872; COSMIC: COSV53937872;