chr6-31666832-A-G

Position:

• chr6-31666832-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001320.7(CSNK2B):​c.1A>G​(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: 8.30

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-31666832-A-G is Pathogenic according to our data. Variant chr6-31666832-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 932465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSNK2B	NM_001320.7	c.1A>G	p.Met1?	start_lost	2/7	ENST00000375882.7	NP_001311.3
CSNK2B	NM_001282385.2	c.1A>G	p.Met1?	start_lost	2/7		NP_001269314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSNK2B	ENST00000375882.7	c.1A>G	p.Met1?	start_lost	2/7	1	NM_001320.7	ENSP00000365042	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2020	Has not been previously published as pathogenic or benign to our knowledge; Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2020	- -

Poirier-Bienvenu neurodevelopmental syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed stop lost variant c.1A>G(p.Met1?) in CSNK2B gene has been reported previously in heterozygous state in an individual with Poirier–Bienvenu neurodevelopmental syndrome (Yang Q, et al., 2022). A different aminoacid c.2T>G (p.Met1Arg) is reported as Pathogenic at the same position. The c.1A>G variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. Multiple lines of computational evidence (Polyphen and SIFT) predict a damaging effect on protein structure and function for this variant. The p.Met1? variant is predicted to disrupt the initiation codon, and thus potentially may interfere with protein expression. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;T;T;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;.;.;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Benign	-0.39	T
PROVEAN	Benign	-1.5	N;N;N;N;N;.
REVEL	Uncertain	0.43
Sift	Benign	0.29	T;D;D;D;D;.
Sift4G	Benign	0.65	T;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.
Vest4		0.46
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		0.76
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1801755635; hg19: chr6-31634609;