19-40717149-C-A

Variant names:

• chr19-40717149-C-A
• rs2082192630
• NM_025194.3:c.14C>A

Variant summary

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

The NM_025194.3(ITPKC):​c.14C>A​(p.Pro5Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,074,736 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P5R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: ITPKC NM_025194.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20

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 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 rank	MANE	Protein	UniProt
ITPKC	NM_025194.3	c.14C>A	p.Pro5Gln	missense_variant	Exon 1 of 7	ENST00000263370.3	NP_079470.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPKC	ENST00000263370.3	c.14C>A	p.Pro5Gln	missense_variant	Exon 1 of 7	1	NM_025194.3	ENSP00000263370.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000372 AC: 4 AN: 1074736 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 507786

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: 0.00000436

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.8	L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.39		Loss of catalytic residue at P5 (P = 0.0028);
MVP		0.58
MPC		1.1
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.44
gMVP		0.43

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: rs2082192630; hg19: chr19-41223054;