chr20-486433-C-T

Position:

• chr20-486433-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_177559.3(CSNK2A1):​c.1003G>A​(p.Gly335Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CSNK2A1 NM_177559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.66

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 Uncertain_significance. Variant got 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.113710254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSNK2A1	NM_177559.3	c.1003G>A	p.Gly335Ser	missense_variant	13/14	ENST00000217244.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSNK2A1	ENST00000217244.9	c.1003G>A	p.Gly335Ser	missense_variant	13/14	1	NM_177559.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T;T;T;T;T;.;T;T;.;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	.;.;.;T;T;.;.;.;T;.;T;.;T;.;T;T;T;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.11	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	0.0	N;N;N;.;.;.;N;N;.;.;.;N;.;.;.;.;.;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.060	.;.;.;.;N;D;N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.074
Sift	Benign	0.42	.;.;.;.;T;D;T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.17	.;.;.;T;T;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0	B;B;B;.;.;.;B;B;.;.;.;B;.;.;.;.;.;B;B
Vest4		0.29, 0.29
MutPred		0.23		Gain of phosphorylation at G335 (P = 0.0123);Gain of phosphorylation at G335 (P = 0.0123);Gain of phosphorylation at G335 (P = 0.0123);.;Gain of phosphorylation at G335 (P = 0.0123);.;Gain of phosphorylation at G335 (P = 0.0123);Gain of phosphorylation at G335 (P = 0.0123);.;.;Gain of phosphorylation at G335 (P = 0.0123);Gain of phosphorylation at G335 (P = 0.0123);.;.;.;.;.;Gain of phosphorylation at G335 (P = 0.0123);Gain of phosphorylation at G335 (P = 0.0123);
MVP		0.43
MPC		0.051
ClinPred		0.51	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.22

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: rs2018100818; hg19: chr20-467077;