rs1554169984

Variant names:

• chr6-31667889-G-A
• rs1554169984
• NM_001320.7:c.94G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-31667889-G-A
• chr6-31667889-G-C
• chr6-31667889-G-T

Variant summary

Our verdict is Pathogenic. The variant received 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. D32H) 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:7
• Conservation: PhyloP100: 9.12
• Publications: 1 publications found

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]

CSNK2B Gene-Disease associations (from GenCC):

• Poirier-Bienvenu neurodevelopmental syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Illumina, Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000263020 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr6-31667889-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1676324.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the CSNK2B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.1296 (above the threshold of 3.09). Trascript score misZ: 3.7791 (above the threshold of 3.09). GenCC associations: The gene is linked to Poirier-Bienvenu neurodevelopmental syndrome, autosomal dominant non-syndromic intellectual disability.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 520596.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.94G>A	p.Asp32Asn	missense_variant	Exon 3 of 7	ENST00000375882.7	NP_001311.3
CSNK2B	NM_001282385.2	c.94G>A	p.Asp32Asn	missense_variant	Exon 3 of 7		NP_001269314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSNK2B	ENST00000375882.7	c.94G>A	p.Asp32Asn	missense_variant	Exon 3 of 7	1	NM_001320.7	ENSP00000365042.3
ENSG00000263020	ENST00000375880.6	c.94G>A	p.Asp32Asn	missense_variant	Exon 3 of 8	3		ENSP00000365040.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 16, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Sep 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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"). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 520596). 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. This variant is not present in population databases (ExAC no frequency). 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. -

Poirier-Bienvenu neurodevelopmental syndrome Pathogenic:2

Aug 13, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP2 supporting -

Jun 11, 2024

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Sep 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.94G>A (p.D32N) alteration is located in exon 3 (coding exon 2) of the CSNK2B gene. This alteration results from a G to A substitution at nucleotide position 94, causing the aspartic acid (D) at amino acid position 32 to be replaced by an asparagine (N). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with CSNK2B-related neurodevelopmental disease (Asif, 2022; Hiraide, 2021; Ernst, 2021). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Functional studies suggest that this variant results in loss of function; however, additional evidence is needed to confirm this finding (Asif, 2022). The in silico prediction for the p.D32N alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

CSNK2B-related disorder Pathogenic:1

Feb 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 11, 2022

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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

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;.;.
PhyloP100		9.1
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
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs1554169984; hg19: chr6-31635666;