6-31667889-G-A

Variant names:

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

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:8
• 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: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSNK2B	NM_001320.7	MANE Select	c.94G>A	p.Asp32Asn	missense	Exon 3 of 7	NP_001311.3
	CSNK2B	NM_001282385.2		c.94G>A	p.Asp32Asn	missense	Exon 3 of 7	NP_001269314.1	A0A1U9X7J2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSNK2B	ENST00000375882.7	TSL:1 MANE Select	c.94G>A	p.Asp32Asn	missense	Exon 3 of 7	ENSP00000365042.3	P67870
	ENSG00000263020	ENST00000617558.2	TSL:1	c.94G>A	p.Asp32Asn	missense	Exon 2 of 6	ENSP00000483989.2	N0E472
	ENSG00000263020	ENST00000375880.6	TSL:3	c.94G>A	p.Asp32Asn	missense	Exon 3 of 8	ENSP00000365040.2	Q5SRQ3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Poirier-Bienvenu neurodevelopmental syndrome (3)
2	-	-	not provided (2)
1	-	-	CSNK2B-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	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 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.95		Loss of ubiquitination at K33 (P = 0.1055)
MVP		0.73
MPC		2.8
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;