20-484049-G-T

Variant names:

• chr20-484049-G-T
• rs1193280723
• NM_177559.3:c.1088C>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Moderate BS2

The NM_177559.3(CSNK2A1):​c.1088C>A​(p.Pro363His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CSNK2A1 NM_177559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.03

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_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 syndromic intellectual disability, Okur-Chung neurodevelopmental syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25187397).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSNK2A1	NM_177559.3	c.1088C>A	p.Pro363His	missense_variant	Exon 14 of 14	ENST00000217244.9	NP_808227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSNK2A1	ENST00000217244.9	c.1088C>A	p.Pro363His	missense_variant	Exon 14 of 14	1	NM_177559.3	ENSP00000217244.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458424 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 725548

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Okur-Chung neurodevelopmental syndrome Uncertain:1

Oct 03, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;T;T;.;T;T;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	.;.;.;.;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.69	N;N;N;.;N;N;.;.;N;.;.;.;.;.;N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.28	.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.19
Sift	Uncertain	0.0030	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.036	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.21	B;B;B;.;B;B;.;.;B;.;.;.;.;.;B;B
Vest4		0.32
MutPred		0.13		Loss of glycosylation at P363 (P = 0.062);Loss of glycosylation at P363 (P = 0.062);Loss of glycosylation at P363 (P = 0.062);.;Loss of glycosylation at P363 (P = 0.062);Loss of glycosylation at P363 (P = 0.062);.;.;Loss of glycosylation at P363 (P = 0.062);.;.;.;.;.;Loss of glycosylation at P363 (P = 0.062);Loss of glycosylation at P363 (P = 0.062);
MVP		0.64
MPC		0.15
ClinPred		0.48	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.28
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1193280723; hg19: chr20-464693;