19-40725090-A-G

Variant names:

• chr19-40725090-A-G
• rs2303723
• NM_025194.3:c.1156-250A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025194.3(ITPKC):​c.1156-250A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0963 in 152,188 control chromosomes in the GnomAD database, including 1,037 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.096 (1037 hom., cov: 31)
• Consequence: ITPKC NM_025194.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 7 publications found

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]

COQ8B Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• nephrotic syndrome, type 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPKC	NM_025194.3	c.1156-250A>G		intron_variant	Intron 1 of 6	ENST00000263370.3	NP_079470.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPKC	ENST00000263370.3	c.1156-250A>G		intron_variant	Intron 1 of 6	1	NM_025194.3	ENSP00000263370.1

Frequencies

GnomAD3 genomes AF: 0.0962 AC: 14625 AN: 152070 Hom.: 1031 Cov.: 31

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0486

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.0501

Gnomad FIN AF: 0.0794

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0480

Gnomad OTH AF: 0.0759

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0963 AC: 14655 AN: 152188 Hom.: 1037 Cov.: 31 AF XY: 0.0965 AC XY: 7184 AN XY: 74422

African (AFR) AF: 0.192 AC: 7962 AN: 41496

American (AMR) AF: 0.0486 AC: 742 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 215 AN: 3470

East Asian (EAS) AF: 0.222 AC: 1148 AN: 5174

South Asian (SAS) AF: 0.0493 AC: 238 AN: 4826

European-Finnish (FIN) AF: 0.0794 AC: 842 AN: 10608

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0480 AC: 3262 AN: 68010

Other (OTH) AF: 0.0761 AC: 161 AN: 2116

Alfa AF: 0.0728 Hom.: 88

Bravo AF: 0.101

Asia WGS AF: 0.130 AC: 450 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.29
DANN	Benign	0.40
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2303723; hg19: chr19-41230995;