chr1-226735627-G-A

Position:

• chr1-226735627-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002221.4(ITPKB):​c.1832C>T​(p.Ser611Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPKB NM_002221.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPKB	NM_002221.4	c.1832C>T	p.Ser611Phe	missense_variant	2/8	ENST00000429204.6	NP_002212.3
ITPKB	NM_001388404.1	c.1832C>T	p.Ser611Phe	missense_variant	2/3		NP_001375333.1
ITPKB	XM_017001211.3	c.1832C>T	p.Ser611Phe	missense_variant	2/3		XP_016856700.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPKB	ENST00000429204.6	c.1832C>T	p.Ser611Phe	missense_variant	2/8	5	NM_002221.4	ENSP00000411152.1
ITPKB	ENST00000272117.8	c.1832C>T	p.Ser611Phe	missense_variant	2/8	1		ENSP00000272117.3
ITPKB	ENST00000366784.1	c.1832C>T	p.Ser611Phe	missense_variant	2/3	1		ENSP00000355748.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Dec 19, 2023

The c.1832C>T (p.S611F) 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 1832, causing the serine (S) at amino acid position 611 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	0.66
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.9	L;L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.54
MutPred		0.24		Loss of phosphorylation at S611 (P = 0.0017);Loss of phosphorylation at S611 (P = 0.0017);Loss of phosphorylation at S611 (P = 0.0017);
MVP		0.61
MPC		1.9
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.64
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-226923328;