rs34491089

Positions:

• chr3-4788027-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 129300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4788027-A-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.6696A>G	p.Lys2232Lys	synonymous_variant	52/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.6651A>G	p.Lys2217Lys	synonymous_variant	51/61		NP_001161744.1
ITPR1	NM_001099952.4	c.6552A>G	p.Lys2184Lys	synonymous_variant	49/59		NP_001093422.2
ITPR1	NM_002222.7	c.6507A>G	p.Lys2169Lys	synonymous_variant	48/58		NP_002213.5

Ensembl

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

GnomAD3 exomes AF: 0.0302 AC: 7474 AN: 247118 Hom.: 176 AF XY: 0.0302 AC XY: 4045 AN XY: 133916

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 SAS exome AF: 0.0447

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

Gnomad4 AFR exome AF: 0.00379

Gnomad4 AMR exome AF: 0.0591

Gnomad4 ASJ exome AF: 0.0258

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0454

Gnomad4 FIN exome AF: 0.0417

Gnomad4 NFE exome AF: 0.0248

Gnomad4 OTH exome AF: 0.0250

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

Gnomad4 AFR AF: 0.00418

Gnomad4 AMR AF: 0.0354

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0469

Gnomad4 FIN AF: 0.0409

Gnomad4 NFE AF: 0.0254

Gnomad4 OTH AF: 0.0180

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 21, 2023	- -

ITPR1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2019

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

LitVar

Other links and lift over

dbSNP: rs34491089; hg19: chr3-4829711;