19-40717864-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025194.3(ITPKC):c.729G>T(p.Glu243Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,613,996 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: ITPKC NM_025194.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.355

Genes affected

ITPKC (HGNC:14897): (inositol-trisphosphate 3-kinase C) This gene encodes a member of the inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] 3-kinase family of enzymes that catalyze the phosphorylation of inositol 1,4,5-trisphosphate to 1,3,4,5-tetrakisphosphate. The encoded protein is localized to the nucleus and cytoplasm and has both nuclear import and nuclear export activity. Single nucleotide polymorphisms in this gene are associated with Kawasaki disease.[provided by RefSeq, Sep 2009]

COQ8B (HGNC:19041): (coenzyme Q8B) This gene encodes a protein with two copies of a domain found in protein kinases. The encoded protein has a complete protein kinase catalytic domain, and a truncated domain that contains only the active and binding sites of the protein kinase domain, however, it is not known whether the protein has any kinase activity. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006312728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPKC	NM_025194.3	c.729G>T	p.Glu243Asp	missense_variant	1/7	ENST00000263370.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPKC	ENST00000263370.3	c.729G>T	p.Glu243Asp	missense_variant	1/7	1	NM_025194.3	P1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000362 AC: 91 AN: 251386 Hom.: 1 AF XY: 0.000353 AC XY: 48 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000214 AC: 313 AN: 1461876 Hom.: 1 Cov.: 32 AF XY: 0.000220 AC XY: 160 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00501

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74314

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000394 Hom.: 1

Bravo AF: 0.000298

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000338 AC: 41

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000593

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 18, 2023

The c.729G>T (p.E243D) alteration is located in exon 1 (coding exon 1) of the ITPKC gene. This alteration results from a G to T substitution at nucleotide position 729, causing the glutamic acid (E) at amino acid position 243 to be replaced by an aspartic acid (D). 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	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	10
Dann	Benign	0.56
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.016
Sift	Uncertain	0.011	D
Sift4G	Benign	0.27	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.16		Loss of sheet (P = 0.0457);
MVP		0.31
MPC		0.37
ClinPred		0.045	T
GERP RS		-0.28
Varity_R		0.093
gMVP		0.085

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: rs145872081; hg19: chr19-41223769; COSMIC: COSV99648412; COSMIC: COSV99648412;