chr20-478765-C-CAAAA

Variant names:

• chr20-478765-C-CAAAA
• rs750062577
• NM_177559.3:c.*5192_*5195dupTTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000400227.8(CSNK2A1):​c.1061-9_1061-6dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 175,820 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (1 hom., cov: 27)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: CSNK2A1 ENST00000400227.8 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 20-478765-C-CAAAA is Benign according to our data. Variant chr20-478765-C-CAAAA is described in ClinVar as Likely_benign. ClinVar VariationId is 2652128.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000228 (26/113926) while in subpopulation AFR AF = 0.000698 (22/31502). AF 95% confidence interval is 0.000473. There are 1 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 26 AD gene.

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.*5192_*5195dupTTTT		3_prime_UTR	Exon 14 of 14	NP_808227.1	P68400-1
	CSNK2A1	NM_001895.4		c.*5192_*5195dupTTTT		3_prime_UTR	Exon 13 of 13	NP_001886.1	P68400-1
	CSNK2A1	NM_177560.3		c.*5192_*5195dupTTTT		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.*5192_*5195dupTTTT		3_prime_UTR	Exon 14 of 14	ENSP00000217244.3	P68400-1
	CSNK2A1	ENST00000400227.8	TSL:1	c.1061-9_1061-6dupTTTT		splice_region intron	N/A	ENSP00000383086.3	E7EU96
	CSNK2A1	ENST00000646561.1		c.*5192_*5195dupTTTT		3_prime_UTR	Exon 13 of 13	ENSP00000496569.1	P68400-1

Frequencies

GnomAD3 genomes AF: 0.000219 AC: 25 AN: 113948 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.000668

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000176

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000192

Gnomad OTH AF: 0.000663

GnomAD4 exome AF: 0.000291 AC: 18 AN: 61894 Hom.: 0 Cov.: 0 AF XY: 0.000247 AC XY: 9 AN XY: 36460

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

African (AFR) AF: 0.00 AC: 0 AN: 316

American (AMR) AF: 0.000704 AC: 1 AN: 1420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1098

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

South Asian (SAS) AF: 0.000444 AC: 8 AN: 18036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 178

European-Non Finnish (NFE) AF: 0.000236 AC: 8 AN: 33964

Other (OTH) AF: 0.000370 AC: 1 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: 0.000228 AC: 26 AN: 113926 Hom.: 1 Cov.: 27 AF XY: 0.000313 AC XY: 17 AN XY: 54250

African (AFR) AF: 0.000698 AC: 22 AN: 31502

American (AMR) AF: 0.000176 AC: 2 AN: 11366

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: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000192 AC: 1 AN: 52152

Other (OTH) AF: 0.000661 AC: 1 AN: 1512

Alfa AF: 0.00 Hom.: 8

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.068
Mutation Taster		=94/6	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;