20-483978-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_177559.3(CSNK2A1):c.1159G>A(p.Ala387Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,611,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: CSNK2A1 NM_177559.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.48

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CSNK2A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.00976795).
• BP6: Variant 20-483978-C-T is Benign according to our data. Variant chr20-483978-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1261752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000361 (55/152282) while in subpopulation AMR AF= 0.000784 (12/15302). AF 95% confidence interval is 0.000452. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSNK2A1	NM_177559.3	c.1159G>A	p.Ala387Thr	missense_variant	14/14	ENST00000217244.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSNK2A1	ENST00000217244.9	c.1159G>A	p.Ala387Thr	missense_variant	14/14	1	NM_177559.3	P1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000245 AC: 61 AN: 249080 Hom.: 0 AF XY: 0.000230 AC XY: 31 AN XY: 134860

Gnomad AFR exome AF: 0.0000636

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00381

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000160 AC: 233 AN: 1459176 Hom.: 0 Cov.: 30 AF XY: 0.000154 AC XY: 112 AN XY: 725906

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000337

Gnomad4 ASJ exome AF: 0.00385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000846

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74454

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000737 Hom.: 0

Bravo AF: 0.000476

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000297 AC: 36

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T;T;.;T;T;.;.;T;.;.;.;.;.;T;T
Eigen	Benign	-0.051
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0098	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.20	N;N;N;.;N;N;.;.;N;.;.;.;.;.;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
Polyphen		0.0010	B;B;B;.;B;B;.;.;B;.;.;.;.;.;B;B
Vest4		0.26
MutPred		0.16		Gain of glycosylation at A387 (P = 0.0128);Gain of glycosylation at A387 (P = 0.0128);Gain of glycosylation at A387 (P = 0.0128);.;Gain of glycosylation at A387 (P = 0.0128);Gain of glycosylation at A387 (P = 0.0128);.;.;Gain of glycosylation at A387 (P = 0.0128);.;.;.;.;.;Gain of glycosylation at A387 (P = 0.0128);Gain of glycosylation at A387 (P = 0.0128);
MVP		0.68
MPC		0.050
ClinPred		0.023	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.080
gMVP		0.39

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: rs199715749; hg19: chr20-464622;