1-226735660-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002221.4(ITPKB):c.1799C>T(p.Ser600Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ITPKB NM_002221.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.12

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3672738).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPKB	NM_002221.4	c.1799C>T	p.Ser600Phe	missense_variant	2/8	ENST00000429204.6
ITPKB	NM_001388404.1	c.1799C>T	p.Ser600Phe	missense_variant	2/3
ITPKB	XM_017001211.3	c.1799C>T	p.Ser600Phe	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPKB	ENST00000429204.6	c.1799C>T	p.Ser600Phe	missense_variant	2/8	5	NM_002221.4	P1
ITPKB	ENST00000272117.8	c.1799C>T	p.Ser600Phe	missense_variant	2/8	1		P1
ITPKB	ENST00000366784.1	c.1799C>T	p.Ser600Phe	missense_variant	2/3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459548 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 725962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2023

The c.1799C>T (p.S600F) 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 1799, causing the serine (S) at amino acid position 600 to be replaced by a phenylalanine (F). 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	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.47
MutPred		0.27		Loss of phosphorylation at S600 (P = 0.006);Loss of phosphorylation at S600 (P = 0.006);Loss of phosphorylation at S600 (P = 0.006);
MVP		0.58
MPC		1.9
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.69
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-226923361;