1-226735804-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002221.4(ITPKB):c.1655C>A(p.Pro552Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.95 in 1,607,554 control chromosomes in the GnomAD database, including 726,057 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.96 (70335 hom., cov: 31)
  • Exomes 𝑓: 0.95 (655722 hom.)
• Consequence: ITPKB NM_002221.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:1
• Conservation: PhyloP100: -0.492

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.0402823E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPKB	NM_002221.4	c.1655C>A	p.Pro552Gln	missense_variant	2/8	ENST00000429204.6
ITPKB	NM_001388404.1	c.1655C>A	p.Pro552Gln	missense_variant	2/3
ITPKB	XM_017001211.3	c.1655C>A	p.Pro552Gln	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPKB	ENST00000429204.6	c.1655C>A	p.Pro552Gln	missense_variant	2/8	5	NM_002221.4	P1
ITPKB	ENST00000272117.8	c.1655C>A	p.Pro552Gln	missense_variant	2/8	1		P1
ITPKB	ENST00000366784.1	c.1655C>A	p.Pro552Gln	missense_variant	2/3	1

Frequencies

GnomAD3 genomes AF: 0.961 AC: 146198 AN: 152142 Hom.: 70276 Cov.: 31

Gnomad AFR AF: 0.989

Gnomad AMI AF: 0.979

Gnomad AMR AF: 0.959

Gnomad ASJ AF: 0.986

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.993

Gnomad FIN AF: 0.959

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.938

Gnomad OTH AF: 0.957

GnomAD3 exomes AF: 0.964 AC: 241547 AN: 250586 Hom.: 116476 AF XY: 0.964 AC XY: 130582 AN XY: 135442

Gnomad AFR exome AF: 0.991

Gnomad AMR exome AF: 0.975

Gnomad ASJ exome AF: 0.984

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.991

Gnomad FIN exome AF: 0.956

Gnomad NFE exome AF: 0.943

Gnomad OTH exome AF: 0.959

GnomAD4 exome AF: 0.949 AC: 1381154 AN: 1455294 Hom.: 655722 Cov.: 55 AF XY: 0.950 AC XY: 686420 AN XY: 722484

Gnomad4 AFR exome AF: 0.992

Gnomad4 AMR exome AF: 0.974

Gnomad4 ASJ exome AF: 0.983

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.991

Gnomad4 FIN exome AF: 0.956

Gnomad4 NFE exome AF: 0.940

Gnomad4 OTH exome AF: 0.957

GnomAD4 genome AF: 0.961 AC: 146316 AN: 152260 Hom.: 70335 Cov.: 31 AF XY: 0.963 AC XY: 71688 AN XY: 74430

Gnomad4 AFR AF: 0.989

Gnomad4 AMR AF: 0.959

Gnomad4 ASJ AF: 0.986

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.993

Gnomad4 FIN AF: 0.959

Gnomad4 NFE AF: 0.938

Gnomad4 OTH AF: 0.958

Alfa AF: 0.948 Hom.: 130744

Bravo AF: 0.964

TwinsUK AF: 0.945 AC: 3503

ALSPAC AF: 0.946 AC: 3644

ESP6500AA AF: 0.991 AC: 4368

ESP6500EA AF: 0.942 AC: 8102

ExAC AF: 0.965 AC: 117098

Asia WGS AF: 0.997 AC: 3466 AN: 3478

EpiCase AF: 0.941

EpiControl AF: 0.947

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Myeloproliferative neoplasm, unclassifiable Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology

Aug 25, 2022

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 94. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.8
Dann	Benign	0.45
DEOGEN2	Benign	0.021	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
MetaRNN	Benign	6.0e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.53	N;N;N
REVEL	Benign	0.010
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.025
MPC		0.18
ClinPred		0.0023	T
GERP RS		-5.0
Varity_R		0.040
gMVP		0.056

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

Other links and lift over

dbSNP: rs708776; hg19: chr1-226923505;