chr20-486423-C-G

Position:

• chr20-486423-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_177559.3(CSNK2A1):​c.1013G>C​(p.Ser338Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S338N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CSNK2A1 NM_177559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.128

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 -5 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07613236).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSNK2A1	NM_177559.3	c.1013G>C	p.Ser338Thr	missense_variant	13/14	ENST00000217244.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSNK2A1	ENST00000217244.9	c.1013G>C	p.Ser338Thr	missense_variant	13/14	1	NM_177559.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251384 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461646 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 727120

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: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Okur-Chung neurodevelopmental syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The observed missense c.1013G>C(p.Ser338Thr) variant in gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant has been reported with allele frequency of 0.0008% in gnomAD Exomes. This variant has not been submitted to the ClinVar database. The amino acid change p.Ser338Thr in CSNK2A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 338 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.35	T;T;T;T;T;.;T;T;.;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	.;.;.;T;T;.;.;.;T;.;T;.;T;.;T;T;T;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.076	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N;N;.;.;.;N;N;.;.;.;N;.;.;.;.;.;N;N
MutationTaster	Benign	0.74	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.56	.;.;.;.;N;.;N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.050
Sift	Benign	0.12	.;.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.081	.;.;.;T;T;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0	B;B;B;.;.;.;B;B;.;.;.;B;.;.;.;.;.;B;B
Vest4		0.28, 0.28
MutPred		0.21		Loss of phosphorylation at S338 (P = 0.0517);Loss of phosphorylation at S338 (P = 0.0517);Loss of phosphorylation at S338 (P = 0.0517);.;Loss of phosphorylation at S338 (P = 0.0517);.;Loss of phosphorylation at S338 (P = 0.0517);Loss of phosphorylation at S338 (P = 0.0517);.;.;Loss of phosphorylation at S338 (P = 0.0517);Loss of phosphorylation at S338 (P = 0.0517);.;.;.;.;.;Loss of phosphorylation at S338 (P = 0.0517);Loss of phosphorylation at S338 (P = 0.0517);
MVP		0.62
MPC		0.048
ClinPred		0.10	T
GERP RS		2.2
Varity_R		0.044
gMVP		0.17

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: rs191244406; hg19: chr20-467067;