20-505182-T-G

Position:

• chr20-505182-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_177559.3(CSNK2A1):​c.149A>C​(p.Tyr50Ser) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y50C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CSNK2A1 NM_177559.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.00

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-505182-T-C is described in Lovd as [Pathogenic].
• 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, 0.93
• PP5: Variant 20-505182-T-G is Pathogenic according to our data. Variant chr20-505182-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 224800.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSNK2A1	NM_177559.3	c.149A>C	p.Tyr50Ser	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.149A>C	p.Tyr50Ser	missense_variant	4/14	1	NM_177559.3	ENSP00000217244.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Okur-Chung neurodevelopmental syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 05, 2016	- -
Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	May 04, 2018	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-05-04 and interpreted as Pathogenic. Variant was initially reported on 2015-10-24 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -

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	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T;T;T;T;T;.;.;.;T;.;.;.;T;T;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;.;D;.;.;D;.;D;.;D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.10	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	-1.1	T
MutationAssessor	Benign	1.7	L;L;L;.;L;L;.;.;.;L;.;.;.;L;L;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.4	.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0030	.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;D;.;D;D;.;.;.;D;.;.;.;D;D;.;.;.;.;.;.;.;.;.
Vest4		0.93, 0.93
MutPred		0.81		Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);Gain of disorder (P = 0.0079);
MVP		0.93
MPC		3.5
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.99
gMVP		0.91

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: rs869312849; hg19: chr20-485826;