Variant chr1-226735691-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_002221.4(ITPKB):c.1768C>T(p.Arg590Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,601,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

ITPKB
NM_002221.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.85

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03473583).

BS2

High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPKB	NM_002221.4 link	c.1768C>T	p.Arg590Trp	missense_variant	2/8	ENST00000429204.6	NP_002212.3	P27987-1B2R9J0
ITPKB	NM_001388404.1 link	c.1768C>T	p.Arg590Trp	missense_variant	2/3		NP_001375333.1
ITPKB	XM_017001211.3 link	c.1768C>T	p.Arg590Trp	missense_variant	2/3		XP_016856700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ITPKB	ENST00000429204.6 link	c.1768C>T	p.Arg590Trp	missense_variant	2/8	5	NM_002221.4	ENSP00000411152.1	P27987-1
ITPKB	ENST00000272117.8 link	c.1768C>T	p.Arg590Trp	missense_variant	2/8	1		ENSP00000272117.3	P27987-1
ITPKB	ENST00000366784.1 link	c.1768C>T	p.Arg590Trp	missense_variant	2/3	1		ENSP00000355748.1	P27987-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000108

AC:

AN:

240710

Hom.:

AF XY:

0.0000614

AC XY:

AN XY:

130188

show subpopulations

Gnomad AFR exome

AF:

0.0000624

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000721

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000101

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.0000766

AC:

111

AN:

1449122

Hom.:

Cov.:

AF XY:

0.0000667

AC XY:

AN XY:

719668

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.0000233

Gnomad4 ASJ exome

AF:

0.0000395

Gnomad4 EAS exome

AF:

0.000885

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.0000588

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000674

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.1768C>T (p.R590W) alteration is located in exon 2 (coding exon 1) of the ITPKB gene. This alteration results from a C to T substitution at nucleotide position 1768, causing the arginine (R) at amino acid position 590 to be replaced by a tryptophan (W). 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

0.075

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

T;T;.

Eigen

Benign

0.0075

Eigen_PC

Benign

-0.048

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.82

.;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.035

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.6

L;L;L

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

N;N;D

REVEL

Benign

0.11

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.080

MutPred

0.23

Loss of methylation at R590 (P = 0.0656);Loss of methylation at R590 (P = 0.0656);Loss of methylation at R590 (P = 0.0656);

MVP

0.23

MPC

0.45

ClinPred

0.20

GERP RS

5.6

Varity_R

0.17

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over