Genetic Variant ITPR1:p.Lys2563Lys (chr3-4814550-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001378452.1(ITPR1):c.7689G>A(p.Lys2563Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.607 in 1,590,260 control chromosomes in the GnomAD database, including 291,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 26468 hom., cov: 24)

Exomes 𝑓: 0.61 ( 265457 hom. )

Consequence

ITPR1
NM_001378452.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.44

Publications

31 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 3-4814550-G-A is Benign according to our data. Variant chr3-4814550-G-A is described in ClinVar as Benign. ClinVar VariationId is 129304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.44 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 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.7689G>A	p.Lys2563Lys	synonymous	Exon 58 of 62	NP_001365381.1
ITPR1	NM_001168272.2		c.7644G>A	p.Lys2548Lys	synonymous	Exon 57 of 61	NP_001161744.1
ITPR1	NM_001099952.4		c.7545G>A	p.Lys2515Lys	synonymous	Exon 55 of 59	NP_001093422.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ITPR1	ENST00000649015.2	MANE Select	c.7689G>A	p.Lys2563Lys	synonymous	Exon 58 of 62	ENSP00000497605.1
ITPR1	ENST00000354582.12	TSL:5	c.7665G>A	p.Lys2555Lys	synonymous	Exon 58 of 62	ENSP00000346595.8
ITPR1	ENST00000648266.1		c.7662G>A	p.Lys2554Lys	synonymous	Exon 58 of 62	ENSP00000498014.1

Frequencies

GnomAD3 genomes

AF:

0.595

AC:

88686

AN:

148982

Hom.:

26453

Cov.:

show subpopulations

Gnomad AFR

AF:

0.563

Gnomad AMI

AF:

0.664

Gnomad AMR

AF:

0.550

Gnomad ASJ

AF:

0.592

Gnomad EAS

AF:

0.722

Gnomad SAS

AF:

0.594

Gnomad FIN

AF:

0.646

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.607

Gnomad OTH

AF:

0.599

GnomAD2 exomes

AF:

0.604

AC:

149857

AN:

248248

AF XY:

0.605

show subpopulations

Gnomad AFR exome

AF:

0.556

Gnomad AMR exome

AF:

0.525

Gnomad ASJ exome

AF:

0.586

Gnomad EAS exome

AF:

0.738

Gnomad FIN exome

AF:

0.642

Gnomad NFE exome

AF:

0.612

Gnomad OTH exome

AF:

0.601

GnomAD4 exome

AF:

0.608

AC:

876888

AN:

1441170

Hom.:

265457

Cov.:

AF XY:

0.609

AC XY:

436309

AN XY:

716730

show subpopulations

African (AFR)

AF:

0.568

AC:

18559

AN:

32646

American (AMR)

AF:

0.534

AC:

23459

AN:

43944

Ashkenazi Jewish (ASJ)

AF:

0.605

AC:

15383

AN:

25426

East Asian (EAS)

AF:

0.722

AC:

27891

AN:

38652

South Asian (SAS)

AF:

0.594

AC:

50943

AN:

85706

European-Finnish (FIN)

AF:

0.653

AC:

33862

AN:

51844

Middle Eastern (MID)

AF:

0.618

AC:

3401

AN:

5506

European-Non Finnish (NFE)

AF:

0.608

AC:

667554

AN:

1098430

Other (OTH)

AF:

0.607

AC:

35836

AN:

59016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

15498

30996

46494

61992

77490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18150

36300

54450

72600

90750

<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:

0.595

AC:

88729

AN:

149090

Hom.:

26468

Cov.:

AF XY:

0.594

AC XY:

43117

AN XY:

72560

show subpopulations

African (AFR)

AF:

0.563

AC:

22746

AN:

40368

American (AMR)

AF:

0.549

AC:

8176

AN:

14880

Ashkenazi Jewish (ASJ)

AF:

0.592

AC:

2043

AN:

3450

East Asian (EAS)

AF:

0.722

AC:

3570

AN:

4948

South Asian (SAS)

AF:

0.594

AC:

2784

AN:

4686

European-Finnish (FIN)

AF:

0.646

AC:

6488

AN:

10046

Middle Eastern (MID)

AF:

0.500

AC:

146

AN:

292

European-Non Finnish (NFE)

AF:

0.607

AC:

40964

AN:

67468

Other (OTH)

AF:

0.592

AC:

1218

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1626

3252

4878

6504

8130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

756

1512

2268

3024

3780

<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:

0.598

Hom.:

59277

Bravo

AF:

0.591

Asia WGS

AF:

0.591

AC:

2056

AN:

3478

EpiCase

AF:

0.601

EpiControl

AF:

0.614

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:4

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 15, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Gillespie syndrome

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Spinocerebellar ataxia type 29

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal dominant cerebellar ataxia

Benign:1

Jan 12, 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.

Spinocerebellar ataxia type 15/16

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

9.7

(source)

DANN

Benign

0.89

PhyloP100

1.4

PromoterAI

-0.056

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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