19-40718299-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_025194.3(ITPKC):c.1155+9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,503,416 control chromosomes in the GnomAD database, including 12,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.10 ( 1034 hom., cov: 32)

Exomes 𝑓: 0.13 ( 11418 hom. )

Consequence

ITPKC
NM_025194.3 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided U:1B:1

Conservation

PhyloP100: 0.915

Publications

89 publications found

Variant links:

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]

ITPKC links:

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

COQ8B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 19-40718299-G-C is Benign according to our data. Variant chr19-40718299-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4277.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPKC	NM_025194.3 link	c.1155+9G>C		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 link	c.1155+9G>C		intron_variant	Intron 1 of 6	1	NM_025194.3	ENSP00000263370.1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15556

AN:

152030

Hom.:

1032

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0323

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.144

Gnomad ASJ

AF:

0.114

Gnomad EAS

AF:

0.0745

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.151

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.101

GnomAD2 exomes

AF:

0.121

AC:

20177

AN:

167104

AF XY:

0.122

show subpopulations

Gnomad AFR exome

AF:

0.0300

Gnomad AMR exome

AF:

0.192

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.0675

Gnomad FIN exome

AF:

0.138

Gnomad NFE exome

AF:

0.126

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.128

AC:

172968

AN:

1351266

Hom.:

11418

Cov.:

AF XY:

0.128

AC XY:

84775

AN XY:

661624

show subpopulations

African (AFR)

AF:

0.0275

AC:

828

AN:

30126

American (AMR)

AF:

0.186

AC:

5341

AN:

28752

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

2057

AN:

19804

East Asian (EAS)

AF:

0.120

AC:

4651

AN:

38770

South Asian (SAS)

AF:

0.125

AC:

8774

AN:

70006

European-Finnish (FIN)

AF:

0.145

AC:

5795

AN:

39942

Middle Eastern (MID)

AF:

0.111

AC:

493

AN:

4422

European-Non Finnish (NFE)

AF:

0.130

AC:

138148

AN:

1063616

Other (OTH)

AF:

0.123

AC:

6881

AN:

55828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

7763

15526

23290

31053

38816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5218

10436

15654

20872

26090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.102

AC:

15565

AN:

152150

Hom.:

1034

Cov.:

AF XY:

0.104

AC XY:

7718

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0322

AC:

1338

AN:

41524

American (AMR)

AF:

0.144

AC:

2200

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

397

AN:

3470

East Asian (EAS)

AF:

0.0744

AC:

385

AN:

5174

South Asian (SAS)

AF:

0.118

AC:

570

AN:

4824

European-Finnish (FIN)

AF:

0.151

AC:

1604

AN:

10594

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.129

AC:

8802

AN:

67976

Other (OTH)

AF:

0.0993

AC:

210

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

716

1432

2148

2864

3580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.123

Hom.:

675

Bravo

AF:

0.0977

Asia WGS

AF:

0.0860

AC:

299

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Reclassified - variant of unknown significance

Uncertain:1

Mar 15, 2010

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

ITPKC-related disorder

Benign:1

Nov 15, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

0.92

PromoterAI

0.052

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over