rs34491089

Variant names:

• chr3-4788027-A-G
• rs34491089
• NM_001378452.1:c.6696A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.576
• Publications: 5 publications found

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)

ENSG00000235978 (HGNC:):

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.6696A>G	p.Lys2232Lys	synonymous_variant	Exon 52 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.6651A>G	p.Lys2217Lys	synonymous_variant	Exon 51 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.6552A>G	p.Lys2184Lys	synonymous_variant	Exon 49 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.6507A>G	p.Lys2169Lys	synonymous_variant	Exon 48 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.6696A>G	p.Lys2232Lys	synonymous_variant	Exon 52 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.6672A>G	p.Lys2224Lys	synonymous_variant	Exon 52 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.6669A>G	p.Lys2223Lys	synonymous_variant	Exon 52 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.6654A>G	p.Lys2218Lys	synonymous_variant	Exon 51 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.6651A>G	p.Lys2217Lys	synonymous_variant	Exon 51 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.6624A>G	p.Lys2208Lys	synonymous_variant	Exon 49 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.6552A>G	p.Lys2184Lys	synonymous_variant	Exon 49 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.6507A>G	p.Lys2169Lys	synonymous_variant	Exon 48 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.4458A>G	p.Lys1486Lys	synonymous_variant	Exon 32 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.3996A>G	p.Lys1332Lys	synonymous_variant	Exon 30 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.3603A>G	p.Lys1201Lys	synonymous_variant	Exon 28 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3262 AN: 152222 Hom.: 59 Cov.: 31

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

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.: 30 AF XY: 0.0269 AC XY: 19528 AN XY: 726386

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: 6 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

GnomAD4 genome AF: 0.0214 AC: 3262 AN: 152340 Hom.: 59 Cov.: 31 AF XY: 0.0225 AC XY: 1673 AN XY: 74492

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: 2 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: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0254 AC: 1731 AN: 68032

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.0227 Hom.: 23

Bravo AF: 0.0198

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 04, 2018

GeneDx

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Nov 21, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

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. -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.5
DANN	Benign	0.43
PhyloP100		0.58
Mutation Taster		=99/1	polymorphism (auto)

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: rs34491089; hg19: chr3-4829711;