Genetic Variant ITPR1:p.Lys2232Lys (chr3-4788027-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001378452.1(ITPR1):c.6696A>G(p.Lys2232Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,612,788 control chromosomes in the GnomAD database, including 715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 59 hom., cov: 31)

Exomes 𝑓: 0.026 ( 656 hom. )

Consequence

ITPR1
NM_001378452.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.576

Publications

5 publications found

Variant links:

Genes affected

ITPR1 (HGNC:6180): (inositol 1,4,5-trisphosphate receptor type 1) This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

ITPR1 Gene-Disease associations (from GenCC):

aniridia-cerebellar ataxia-intellectual disability syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
spinocerebellar ataxia type 29
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
spinocerebellar ataxia type 15/16
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ITPR1 links:

ENSG00000235978 (HGNC:):

ENSG00000235978 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 3-4788027-A-G is Benign according to our data. Variant chr3-4788027-A-G is described in ClinVar as Benign. ClinVar VariationId is 129300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.576 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378452.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ITPR1	NM_001378452.1	MANE Select	c.6696A>G	p.Lys2232Lys	synonymous	Exon 52 of 62	NP_001365381.1
ITPR1	NM_001168272.2		c.6651A>G	p.Lys2217Lys	synonymous	Exon 51 of 61	NP_001161744.1
ITPR1	NM_001099952.4		c.6552A>G	p.Lys2184Lys	synonymous	Exon 49 of 59	NP_001093422.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ITPR1	ENST00000649015.2	MANE Select	c.6696A>G	p.Lys2232Lys	synonymous	Exon 52 of 62	ENSP00000497605.1
ITPR1	ENST00000354582.12	TSL:5	c.6672A>G	p.Lys2224Lys	synonymous	Exon 52 of 62	ENSP00000346595.8
ITPR1	ENST00000648266.1		c.6669A>G	p.Lys2223Lys	synonymous	Exon 52 of 62	ENSP00000498014.1

Frequencies

GnomAD3 genomes

AF:

0.0214

AC:

3262

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00420

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0352

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0475

Gnomad FIN

AF:

0.0409

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0254

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0302

AC:

7474

AN:

247118

AF XY:

0.0302

show subpopulations

Gnomad AFR exome

AF:

0.00445

Gnomad AMR exome

AF:

0.0631

Gnomad ASJ exome

AF:

0.0270

Gnomad EAS exome

AF:

0.000335

Gnomad FIN exome

AF:

0.0410

Gnomad NFE exome

AF:

0.0227

Gnomad OTH exome

AF:

0.0326

GnomAD4 exome

AF:

0.0265

AC:

38686

AN:

1460448

Hom.:

656

Cov.:

AF XY:

0.0269

AC XY:

19528

AN XY:

726386

show subpopulations

African (AFR)

AF:

0.00379

AC:

127

AN:

33470

American (AMR)

AF:

0.0591

AC:

2637

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.0258

AC:

675

AN:

26114

East Asian (EAS)

AF:

0.000151

AC:

AN:

39698

South Asian (SAS)

AF:

0.0454

AC:

3900

AN:

85874

European-Finnish (FIN)

AF:

0.0417

AC:

2224

AN:

53370

Middle Eastern (MID)

AF:

0.0179

AC:

103

AN:

5766

European-Non Finnish (NFE)

AF:

0.0248

AC:

27507

AN:

1111218

Other (OTH)

AF:

0.0250

AC:

1507

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1721

3443

5164

6886

8607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1092

2184

3276

4368

5460

<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:

0.0214

AC:

3262

AN:

152340

Hom.:

Cov.:

AF XY:

0.0225

AC XY:

1673

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00418

AC:

174

AN:

41588

American (AMR)

AF:

0.0354

AC:

542

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

103

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0469

AC:

226

AN:

4818

European-Finnish (FIN)

AF:

0.0409

AC:

434

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0254

AC:

1731

AN:

68032

Other (OTH)

AF:

0.0180

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

159

317

476

634

793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0227

Hom.:

Bravo

AF:

0.0198

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Nov 21, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ITPR1-related disorder

Benign:1

Feb 20, 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).

Autosomal dominant cerebellar ataxia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

2.5

(source)

DANN

Benign

0.43

PhyloP100

0.58

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over