NM_001320.7:c.3G>A

Variant names:

• chr6-31666834-G-A
• rs1801756272
• NM_001320.7:c.3G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001320.7(CSNK2B):​c.3G>A​(p.Met1?) variant causes a start lost 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CSNK2B NM_001320.7 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.12

Genes affected

CSNK2B (HGNC:2460): (casein kinase 2 beta) This gene encodes the beta subunit of casein kinase II, a ubiquitous protein kinase which regulates metabolic pathways, signal transduction, transcription, translation, and replication. The enzyme is composed of three subunits, alpha, alpha prime and beta, which form a tetrameric holoenzyme. The alpha and alpha prime subunits are catalytic, while the beta subunit serves regulatory functions. The enzyme localizes to the endoplasmic reticulum and the Golgi apparatus. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

ENSG00000263020 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 52 codons. Genomic position: 31667949. Lost 0.238 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-31666834-G-A is Pathogenic according to our data. Variant chr6-31666834-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3341965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSNK2B	NM_001320.7	c.3G>A	p.Met1?	start_lost	Exon 2 of 7	ENST00000375882.7	NP_001311.3
CSNK2B	NM_001282385.2	c.3G>A	p.Met1?	start_lost	Exon 2 of 7		NP_001269314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSNK2B	ENST00000375882.7	c.3G>A	p.Met1?	start_lost	Exon 2 of 7	1	NM_001320.7	ENSP00000365042.3
ENSG00000263020	ENST00000375880.6	c.3G>A	p.Met1?	start_lost	Exon 2 of 8	3		ENSP00000365040.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Sep 13, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34370157) -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CSNK2B: PM2, PS1:Moderate, PS2:Moderate, PVS1:Moderate, PS4:Supporting -

Poirier-Bienvenu neurodevelopmental syndrome Pathogenic:1

Oct 31, 2023

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This start loss variant affects the translation initiation codon (p.Met1) and is therefore predicted to lead to a complete absence of the CSNK2B protein. This variant has been previously reported as a de novo heterozygous change in patients with Poirier-Bienvenu neurodevelopmental syndrome (PMID: 34370157). Other variants that result in the loss of the (p.Met1) initiation codon have been reported in individuals with neurodevelopmental phenotypes (PMID: 34041744, 35370893). The c.3G>A (p.Met1?) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, c.3G>A (p.Met1?) is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;T;T;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;.;.;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Benign	-0.32	T
PROVEAN	Benign	-1.8	N;N;N;N;N;.
REVEL	Uncertain	0.46
Sift	Benign	0.15	T;D;D;D;D;.
Sift4G	Benign	0.49	T;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.
Vest4		0.45
MutPred		0.99		.;Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);
MVP		0.74
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.49
gMVP		0.69

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: rs1801756272; hg19: chr6-31634611;