chr6-31667889-G-A

Position:

• chr6-31667889-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001320.7(CSNK2B):​c.94G>A​(p.Asp32Asn) variant causes a missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D32A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSNK2B NM_001320.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a chain Casein kinase II subunit beta (size 213) in uniprot entity CSK2B_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_001320.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-31667890-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 3024534.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CSNK2B. . Gene score misZ 3.1296 (greater than the threshold 3.09). Trascript score misZ 3.7791 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant non-syndromic intellectual disability, Poirier-Bienvenu neurodevelopmental syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 6-31667889-G-A is Pathogenic according to our data. Variant chr6-31667889-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSNK2B	NM_001320.7	c.94G>A	p.Asp32Asn	missense_variant	3/7	ENST00000375882.7
CSNK2B	NM_001282385.2	c.94G>A	p.Asp32Asn	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSNK2B	ENST00000375882.7	c.94G>A	p.Asp32Asn	missense_variant	3/7	1	NM_001320.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2021	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33644862, 34041744) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 15, 2021	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 520596). This missense change has been observed in individual(s) with CSNK2B-related conditions (PMID: 33644862, 34041744; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 32 of the CSNK2B protein (p.Asp32Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Poirier-Bienvenu neurodevelopmental syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 13, 2022	ACMG classification criteria: PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP2 supporting -

CSNK2B-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2023

The CSNK2B c.94G>A variant is predicted to result in the amino acid substitution p.Asp32Asn. This variant has been reported de novo in an individual with profound developmental delay, intellectual disability, cerebellar atrophy and additional neurologic features (Tables 2 and S1, Subject 329, Hiraide et al. 2021. PubMed ID: 33644862). This variant has also been reported de novo in an additional individual with moderate intellectual disability, wide-based ataxic gait, mild dysmorphic features, and absence seizures (Table S1, Ernst et al. 2021. PubMed ID: 34041744). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, de novo variants in this gene are commonly reported to be causative for CSNK2B-associated disorders (Okur et al. 2016. PubMed ID: 27048600; Nakashima et al. 2019. PubMed ID: 30655572; Li et al. 2019. PubMed ID: 31784560). This variant is interpreted as likely pathogenic. -

Seizure;C0039075:Syndactyly;C0399526:Mandibular prognathia;C0423224:Deeply set eye;C0424503:Abnormal facial shape;C0426886:Tapered finger;C1168239:Asymmetry of the ears;C1834055:Underdeveloped nasal alae;C1844505:Pointed chin;C1865017:Thin upper lip vermilion;C3714756:Intellectual disability;C4021770:Toe clinodactyly Pathogenic:1

Pathogenic, no assertion criteria provided

research

Cologne Center for Genomics, Faculty of Medicine, University of Cologne

Apr 11, 2022

Causing a new intellectual disability-craniodigital syndrome (IDCS) -

Inborn genetic diseases Uncertain:1

Uncertain significance, flagged submission

clinical testing

Ambry Genetics

Oct 05, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	.;D;D;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;.;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.2	.;M;M;M;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;.
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.
Vest4		0.82
MutPred		0.95		.;Loss of ubiquitination at K33 (P = 0.1055);Loss of ubiquitination at K33 (P = 0.1055);Loss of ubiquitination at K33 (P = 0.1055);Loss of ubiquitination at K33 (P = 0.1055);Loss of ubiquitination at K33 (P = 0.1055);
MVP		0.73
MPC		2.8, 2.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.98

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: rs1554169984; hg19: chr6-31635666;