20-478765-CAAAAAAAA-CAAAAAAAAAAA

Variant names:

• chr20-478765-C-CAAA
• rs750062577
• NM_177559.3:c.*5193_*5195dupTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000400227.8(CSNK2A1):​c.1061-8_1061-6dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 175,738 control chromosomes in the GnomAD database, including 38 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.016 (38 hom., cov: 27)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: CSNK2A1 ENST00000400227.8 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0680
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000400227.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSNK2A1	NM_177559.3	MANE Select	c.*5193_*5195dupTTT		3_prime_UTR	Exon 14 of 14	NP_808227.1	P68400-1
	CSNK2A1	NM_001895.4		c.*5193_*5195dupTTT		3_prime_UTR	Exon 13 of 13	NP_001886.1	P68400-1
	CSNK2A1	NM_177560.3		c.*5193_*5195dupTTT		3_prime_UTR	Exon 12 of 12	NP_808228.1	P68400-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSNK2A1	ENST00000217244.9	TSL:1 MANE Select	c.*5193_*5195dupTTT		3_prime_UTR	Exon 14 of 14	ENSP00000217244.3	P68400-1
	CSNK2A1	ENST00000400227.8	TSL:1	c.1061-8_1061-6dupTTT		splice_region intron	N/A	ENSP00000383086.3	E7EU96
	CSNK2A1	ENST00000646561.1		c.*5193_*5195dupTTT		3_prime_UTR	Exon 13 of 13	ENSP00000496569.1	P68400-1

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 1797 AN: 113916 Hom.: 36 Cov.: 27

Gnomad AFR AF: 0.0540

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00599

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00379

Gnomad NFE AF: 0.000173

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.00126 AC: 78 AN: 61844 Hom.: 0 Cov.: 0 AF XY: 0.00115 AC XY: 42 AN XY: 36432

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00645 AC: 2 AN: 310

American (AMR) AF: 0.00423 AC: 6 AN: 1418

Ashkenazi Jewish (ASJ) AF: 0.00182 AC: 2 AN: 1098

East Asian (EAS) AF: 0.00 AC: 0 AN: 330

South Asian (SAS) AF: 0.00133 AC: 24 AN: 18022

European-Finnish (FIN) AF: 0.00130 AC: 5 AN: 3846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 176

European-Non Finnish (NFE) AF: 0.00103 AC: 35 AN: 33938

Other (OTH) AF: 0.00148 AC: 4 AN: 2706

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0158 AC: 1802 AN: 113894 Hom.: 38 Cov.: 27 AF XY: 0.0151 AC XY: 821 AN XY: 54234

African (AFR) AF: 0.0541 AC: 1704 AN: 31472

American (AMR) AF: 0.00590 AC: 67 AN: 11364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2754

East Asian (EAS) AF: 0.00 AC: 0 AN: 4076

South Asian (SAS) AF: 0.00 AC: 0 AN: 3500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6116

Middle Eastern (MID) AF: 0.00417 AC: 1 AN: 240

European-Non Finnish (NFE) AF: 0.000173 AC: 9 AN: 52152

Other (OTH) AF: 0.0139 AC: 21 AN: 1512

Alfa AF: 0.00 Hom.: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.068
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs750062577; hg19: chr20-459409;