Genetic Variant CSNK2A1:p.Ala349Thr (chr20-486391-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2BP4_ModerateBP6_ModerateBS2

The NM_177559.3(CSNK2A1):c.1045G>A(p.Ala349Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,613,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

CSNK2A1
NM_177559.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.64

Publications

4 publications found

Variant links:

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 Submitted by: Ambry Genetics, G2P, Illumina, Labcorp Genetics (formerly Invitae)
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

CSNK2A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.069675684).

BP6

Variant 20-486391-C-T is Benign according to our data. Variant chr20-486391-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3497841.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177559.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSNK2A1	NM_177559.3	MANE Select	c.1045G>A	p.Ala349Thr	missense	Exon 13 of 14	NP_808227.1	P68400-1
CSNK2A1	NM_001362770.2		c.1045G>A	p.Ala349Thr	missense	Exon 13 of 15	NP_001349699.1	P68400-1
CSNK2A1	NM_001362771.2		c.1045G>A	p.Ala349Thr	missense	Exon 12 of 14	NP_001349700.1	P68400-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSNK2A1	ENST00000217244.9	TSL:1 MANE Select	c.1045G>A	p.Ala349Thr	missense	Exon 13 of 14	ENSP00000217244.3	P68400-1
CSNK2A1	ENST00000400227.8	TSL:1	c.1045G>A	p.Ala349Thr	missense	Exon 12 of 13	ENSP00000383086.3	E7EU96
CSNK2A1	ENST00000349736.10	TSL:1	c.637G>A	p.Ala213Thr	missense	Exon 11 of 12	ENSP00000339247.6	P68400-2

Frequencies

GnomAD3 genomes

AF:

0.0000462

AC:

AN:

151624

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000381

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000119

AC:

AN:

251368

AF XY:

0.000162

show subpopulations

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 FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000862

AC:

126

AN:

1461728

Hom.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.000749

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000675

AC:

AN:

1111888

Other (OTH)

AF:

0.000182

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000462

AC:

AN:

151624

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73998

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41214

American (AMR)

AF:

0.0000659

AC:

AN:

15174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.000381

AC:

AN:

10510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.14

Eigen_PC

Benign

0.067

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.013

MetaRNN

Benign

0.070

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.55

PhyloP100

2.6

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.38

REVEL

Benign

0.10

Sift

Benign

0.18

Sift4G

Benign

0.27

Polyphen

0.0010

Vest4

0.52

MVP

0.53

MPC

0.050

ClinPred

0.10

GERP RS

4.9

Varity_R

0.44

gMVP

0.31

Mutation Taster

=58/42

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over