Genetic Variant ITPKC:p.Ala423Ala (chr19-40729215-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_025194.3(ITPKC):c.1269A>G(p.Ala423Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0631 in 1,613,686 control chromosomes in the GnomAD database, including 4,806 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 ( 1035 hom., cov: 32)

Exomes 𝑓: 0.060 ( 3771 hom. )

Consequence

ITPKC
NM_025194.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.88

Publications

18 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:

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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=-0.78).

BP7

Synonymous conserved (PhyloP=-2.88 with no splicing effect.

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 link	c.1269A>G	p.Ala423Ala	synonymous_variant	Exon 3 of 7	ENST00000263370.3	NP_079470.1	Q96DU7A0A024R0N8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPKC	ENST00000263370.3 link	c.1269A>G	p.Ala423Ala	synonymous_variant	Exon 3 of 7	1	NM_025194.3	ENSP00000263370.1		Q96DU7

Frequencies

GnomAD3 genomes

AF:

0.0962

AC:

14621

AN:

152040

Hom.:

1029

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.0615

Gnomad AMR

AF:

0.0488

Gnomad ASJ

AF:

0.0617

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.0499

Gnomad FIN

AF:

0.0795

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0479

Gnomad OTH

AF:

0.0761

GnomAD2 exomes

AF:

0.0725

AC:

18209

AN:

251242

AF XY:

0.0695

show subpopulations

Gnomad AFR exome

AF:

0.193

Gnomad AMR exome

AF:

0.0293

Gnomad ASJ exome

AF:

0.0608

Gnomad EAS exome

AF:

0.228

Gnomad FIN exome

AF:

0.0871

Gnomad NFE exome

AF:

0.0500

Gnomad OTH exome

AF:

0.0548

GnomAD4 exome

AF:

0.0597

AC:

87191

AN:

1461528

Hom.:

3771

Cov.:

AF XY:

0.0587

AC XY:

42696

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.204

AC:

6810

AN:

33462

American (AMR)

AF:

0.0309

AC:

1380

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0628

AC:

1641

AN:

26124

East Asian (EAS)

AF:

0.236

AC:

9361

AN:

39690

South Asian (SAS)

AF:

0.0445

AC:

3837

AN:

86246

European-Finnish (FIN)

AF:

0.0866

AC:

4621

AN:

53388

Middle Eastern (MID)

AF:

0.0550

AC:

317

AN:

5766

European-Non Finnish (NFE)

AF:

0.0494

AC:

54966

AN:

1111748

Other (OTH)

AF:

0.0705

AC:

4258

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

3964

7928

11893

15857

19821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2296

4592

6888

9184

11480

<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:

0.0963

AC:

14651

AN:

152158

Hom.:

1035

Cov.:

AF XY:

0.0965

AC XY:

7181

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.192

AC:

7963

AN:

41500

American (AMR)

AF:

0.0488

AC:

745

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0617

AC:

214

AN:

3468

East Asian (EAS)

AF:

0.221

AC:

1144

AN:

5166

South Asian (SAS)

AF:

0.0491

AC:

237

AN:

4822

European-Finnish (FIN)

AF:

0.0795

AC:

843

AN:

10598

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0479

AC:

3259

AN:

68008

Other (OTH)

AF:

0.0763

AC:

161

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

651

1303

1954

2606

3257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0632

Hom.:

499

Bravo

AF:

0.101

Asia WGS

AF:

0.130

AC:

451

AN:

3478

EpiCase

AF:

0.0483

EpiControl

AF:

0.0475

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.9

(source)

DANN

Benign

0.46

PhyloP100

-2.9

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over