19-40717152-G-A

Variant names:

• chr19-40717152-G-A
• rs1369523420
• NM_025194.3:c.17G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025194.3(ITPKC):​c.17G>A​(p.Cys6Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000279 in 1,075,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ITPKC NM_025194.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025194.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPKC	NM_025194.3	MANE Select	c.17G>A	p.Cys6Tyr	missense	Exon 1 of 7	NP_079470.1	Q96DU7
	ITPKC	NM_001411098.1		c.17G>A	p.Cys6Tyr	missense	Exon 1 of 6	NP_001398027.1	A0A8V8TPP3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPKC	ENST00000263370.3	TSL:1 MANE Select	c.17G>A	p.Cys6Tyr	missense	Exon 1 of 7	ENSP00000263370.1	Q96DU7
	ITPKC	ENST00000699490.1		c.17G>A	p.Cys6Tyr	missense	Exon 1 of 8	ENSP00000514401.1	Q96DU7
	ITPKC	ENST00000699489.1		c.17G>A	p.Cys6Tyr	missense	Exon 1 of 6	ENSP00000514400.1	A0A8V8TPP3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000279 AC: 3 AN: 1075002 Hom.: 0 Cov.: 30 AF XY: 0.00000197 AC XY: 1 AN XY: 507924

African (AFR) AF: 0.00 AC: 0 AN: 22664

American (AMR) AF: 0.00 AC: 0 AN: 8228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14104

East Asian (EAS) AF: 0.00 AC: 0 AN: 26254

South Asian (SAS) AF: 0.00 AC: 0 AN: 19464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2892

European-Non Finnish (NFE) AF: 0.00000327 AC: 3 AN: 917204

Other (OTH) AF: 0.00 AC: 0 AN: 43258

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.2
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.071	T
Polyphen		0.99	D
Vest4		0.70
MutPred		0.40		Gain of catalytic residue at C6 (P = 0.0463)
MVP		0.64
MPC		1.5
ClinPred		0.94	D
GERP RS		3.8
PromoterAI		-0.034	Neutral
Varity_R		0.85
gMVP		0.32
Mutation Taster		=88/12	polymorphism

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: rs1369523420; hg19: chr19-41223057;