1-226736186-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002221.4(ITPKB):c.1273G>A(p.Glu425Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 1,392,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ITPKB
NM_002221.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.879

Publications

1 publications found

Variant links:

Genes affected

ITPKB (HGNC:6179): (inositol-trisphosphate 3-kinase B) The protein encoded by this protein regulates inositol phosphate metabolism by phosphorylation of second messenger inositol 1,4,5-trisphosphate to Ins(1,3,4,5)P4. The activity of this encoded protein is responsible for regulating the levels of a large number of inositol polyphosphates that are important in cellular signaling. Both calcium/calmodulin and protein phosphorylation mechanisms control its activity. [provided by RefSeq, Jul 2008]

ITPKB Gene-Disease associations (from GenCC):

ITPKB deficiency
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
Tourette syndrome
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ITPKB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041062832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPKB	NM_002221.4 link	c.1273G>A	p.Glu425Lys	missense_variant	Exon 2 of 8	ENST00000429204.6	NP_002212.3	P27987-1B2R9J0
ITPKB	NM_001388404.1 link	c.1273G>A	p.Glu425Lys	missense_variant	Exon 2 of 3		NP_001375333.1
ITPKB	XM_017001211.3 link	c.1273G>A	p.Glu425Lys	missense_variant	Exon 2 of 3		XP_016856700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPKB	ENST00000429204.6 link	c.1273G>A	p.Glu425Lys	missense_variant	Exon 2 of 8	5	NM_002221.4	ENSP00000411152.1	P27987-1
ITPKB	ENST00000272117.8 link	c.1273G>A	p.Glu425Lys	missense_variant	Exon 2 of 8	1		ENSP00000272117.3	P27987-1
ITPKB	ENST00000366784.1 link	c.1273G>A	p.Glu425Lys	missense_variant	Exon 2 of 3	1		ENSP00000355748.1	P27987-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000526

AC:

AN:

190008

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000122

AC:

AN:

1392324

Hom.:

Cov.:

AF XY:

0.0000160

AC XY:

AN XY:

685456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31266

American (AMR)

AF:

0.00

AC:

AN:

34954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21178

East Asian (EAS)

AF:

0.00

AC:

AN:

39222

South Asian (SAS)

AF:

0.000215

AC:

AN:

74302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5392

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1079624

Other (OTH)

AF:

0.00

AC:

AN:

57268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1273G>A (p.E425K) alteration is located in exon 2 (coding exon 1) of the ITPKB gene. This alteration results from a G to A substitution at nucleotide position 1273, causing the glutamic acid (E) at amino acid position 425 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.034

T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.69

.;T;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.041

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.63

N;N;N

PhyloP100

0.88

PrimateAI

Benign

0.43

PROVEAN

Benign

0.23

N;N;N

REVEL

Benign

0.013

Sift

Benign

0.74

T;T;T

Sift4G

Benign

0.90

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.074

MutPred

0.29

Gain of MoRF binding (P = 0.0026);Gain of MoRF binding (P = 0.0026);Gain of MoRF binding (P = 0.0026);

MVP

0.23

MPC

0.22

ClinPred

0.028

GERP RS

2.6

Varity_R

0.035

gMVP

0.21

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over