NM_001320.7:c.94G>C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001320.7(CSNK2B):​c.94G>C​(p.Asp32His) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D32Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSNK2B NM_001320.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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 12 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-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1685680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.979
• PP5: Variant 6-31667889-G-C is Pathogenic according to our data. 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSNK2B	NM_001320.7	MANE Select	c.94G>C	p.Asp32His	missense	Exon 3 of 7	NP_001311.3
	CSNK2B	NM_001282385.2		c.94G>C	p.Asp32His	missense	Exon 3 of 7	NP_001269314.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSNK2B	ENST00000375882.7	TSL:1 MANE Select	c.94G>C	p.Asp32His	missense	Exon 3 of 7	ENSP00000365042.3
	ENSG00000263020	ENST00000617558.2	TSL:1	c.94G>C	p.Asp32His	missense	Exon 2 of 6	ENSP00000483989.2
	ENSG00000263020	ENST00000375880.6	TSL:3	c.94G>C	p.Asp32His	missense	Exon 3 of 8	ENSP00000365040.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability-craniodigital syndrome 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

New intellectual disability-craniodigital syndrome

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		9.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.95		Loss of ubiquitination at K33 (P = 0.0603)
MVP		0.87
MPC		3.1
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.99
Mutation Taster		=16/84	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;